|
Effective concentration against human immunodeficiency virus type 1 G190S mutant strain
|
Human immunodeficiency virus 1
|
0.1
nM
|
|
Journal : J. Med. Chem.
Title : In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine).
Year : 2005
Volume : 48
Issue : 6
First Page : 1901
Last Page : 1909
Authors : Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, Koymans L, Vinkers M, Guillemont J, Pasquier E, Kukla M, Ludovici D, Andries K, de Béthune MP, Pauwels R, Das K, Clark AD, Frenkel YV, Hughes SH, Medaer B, De Knaep F, Bohets H, De Clerck F, Lampo A, Williams P, Stoffels P.
Abstract : Ideally, an anti-HIV drug should (1) be highly active against wild-type and mutant HIV without allowing breakthrough; (2) have high oral bioavailability and long elimination half-life, allowing once-daily oral treatment at low doses; (3) have minimal adverse effects; and (4) be easy to synthesize and formulate. R278474, a new diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitor (NNRTI), appears to meet these criteria and to be suitable for high compliance oral treatment of HIV-1 infection. The discovery of R278474 was the result of a coordinated multidisciplinary effort involving medicinal chemists, virologists, crystallographers, molecular modelers, toxicologists, analytical chemists, pharmacists, and many others.
|
Effective concentration against human immunodeficiency virus type 1 K103N mutant strain
|
Human immunodeficiency virus 1
|
0.3
nM
|
|
Journal : J. Med. Chem.
Title : In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine).
Year : 2005
Volume : 48
Issue : 6
First Page : 1901
Last Page : 1909
Authors : Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, Koymans L, Vinkers M, Guillemont J, Pasquier E, Kukla M, Ludovici D, Andries K, de Béthune MP, Pauwels R, Das K, Clark AD, Frenkel YV, Hughes SH, Medaer B, De Knaep F, Bohets H, De Clerck F, Lampo A, Williams P, Stoffels P.
Abstract : Ideally, an anti-HIV drug should (1) be highly active against wild-type and mutant HIV without allowing breakthrough; (2) have high oral bioavailability and long elimination half-life, allowing once-daily oral treatment at low doses; (3) have minimal adverse effects; and (4) be easy to synthesize and formulate. R278474, a new diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitor (NNRTI), appears to meet these criteria and to be suitable for high compliance oral treatment of HIV-1 infection. The discovery of R278474 was the result of a coordinated multidisciplinary effort involving medicinal chemists, virologists, crystallographers, molecular modelers, toxicologists, analytical chemists, pharmacists, and many others.
|
Effective concentration against human immunodeficiency virus type 1 L100I mutant strain
|
Human immunodeficiency virus 1
|
0.4
nM
|
|
Journal : J. Med. Chem.
Title : In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine).
Year : 2005
Volume : 48
Issue : 6
First Page : 1901
Last Page : 1909
Authors : Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, Koymans L, Vinkers M, Guillemont J, Pasquier E, Kukla M, Ludovici D, Andries K, de Béthune MP, Pauwels R, Das K, Clark AD, Frenkel YV, Hughes SH, Medaer B, De Knaep F, Bohets H, De Clerck F, Lampo A, Williams P, Stoffels P.
Abstract : Ideally, an anti-HIV drug should (1) be highly active against wild-type and mutant HIV without allowing breakthrough; (2) have high oral bioavailability and long elimination half-life, allowing once-daily oral treatment at low doses; (3) have minimal adverse effects; and (4) be easy to synthesize and formulate. R278474, a new diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitor (NNRTI), appears to meet these criteria and to be suitable for high compliance oral treatment of HIV-1 infection. The discovery of R278474 was the result of a coordinated multidisciplinary effort involving medicinal chemists, virologists, crystallographers, molecular modelers, toxicologists, analytical chemists, pharmacists, and many others.
|
Effective concentration against human immunodeficiency virus type 1 Y181C mutant strain
|
Human immunodeficiency virus 1
|
1.3
nM
|
|
Journal : J. Med. Chem.
Title : In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine).
Year : 2005
Volume : 48
Issue : 6
First Page : 1901
Last Page : 1909
Authors : Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, Koymans L, Vinkers M, Guillemont J, Pasquier E, Kukla M, Ludovici D, Andries K, de Béthune MP, Pauwels R, Das K, Clark AD, Frenkel YV, Hughes SH, Medaer B, De Knaep F, Bohets H, De Clerck F, Lampo A, Williams P, Stoffels P.
Abstract : Ideally, an anti-HIV drug should (1) be highly active against wild-type and mutant HIV without allowing breakthrough; (2) have high oral bioavailability and long elimination half-life, allowing once-daily oral treatment at low doses; (3) have minimal adverse effects; and (4) be easy to synthesize and formulate. R278474, a new diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitor (NNRTI), appears to meet these criteria and to be suitable for high compliance oral treatment of HIV-1 infection. The discovery of R278474 was the result of a coordinated multidisciplinary effort involving medicinal chemists, virologists, crystallographers, molecular modelers, toxicologists, analytical chemists, pharmacists, and many others.
|
Effective concentration against human immunodeficiency virus type 1 Y188L mutant strain
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine).
Year : 2005
Volume : 48
Issue : 6
First Page : 1901
Last Page : 1909
Authors : Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, Koymans L, Vinkers M, Guillemont J, Pasquier E, Kukla M, Ludovici D, Andries K, de Béthune MP, Pauwels R, Das K, Clark AD, Frenkel YV, Hughes SH, Medaer B, De Knaep F, Bohets H, De Clerck F, Lampo A, Williams P, Stoffels P.
Abstract : Ideally, an anti-HIV drug should (1) be highly active against wild-type and mutant HIV without allowing breakthrough; (2) have high oral bioavailability and long elimination half-life, allowing once-daily oral treatment at low doses; (3) have minimal adverse effects; and (4) be easy to synthesize and formulate. R278474, a new diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitor (NNRTI), appears to meet these criteria and to be suitable for high compliance oral treatment of HIV-1 infection. The discovery of R278474 was the result of a coordinated multidisciplinary effort involving medicinal chemists, virologists, crystallographers, molecular modelers, toxicologists, analytical chemists, pharmacists, and many others.
|
Effective concentration against rhuman immunodeficiency virus type 1 wild type mutant strain
|
Human immunodeficiency virus 1
|
0.4
nM
|
|
Journal : J. Med. Chem.
Title : In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine).
Year : 2005
Volume : 48
Issue : 6
First Page : 1901
Last Page : 1909
Authors : Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, Koymans L, Vinkers M, Guillemont J, Pasquier E, Kukla M, Ludovici D, Andries K, de Béthune MP, Pauwels R, Das K, Clark AD, Frenkel YV, Hughes SH, Medaer B, De Knaep F, Bohets H, De Clerck F, Lampo A, Williams P, Stoffels P.
Abstract : Ideally, an anti-HIV drug should (1) be highly active against wild-type and mutant HIV without allowing breakthrough; (2) have high oral bioavailability and long elimination half-life, allowing once-daily oral treatment at low doses; (3) have minimal adverse effects; and (4) be easy to synthesize and formulate. R278474, a new diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitor (NNRTI), appears to meet these criteria and to be suitable for high compliance oral treatment of HIV-1 infection. The discovery of R278474 was the result of a coordinated multidisciplinary effort involving medicinal chemists, virologists, crystallographers, molecular modelers, toxicologists, analytical chemists, pharmacists, and many others.
|
Effective concentration against human immunodeficiency virus type 1 K103N and Y181C mutant strains
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine).
Year : 2005
Volume : 48
Issue : 6
First Page : 1901
Last Page : 1909
Authors : Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, Koymans L, Vinkers M, Guillemont J, Pasquier E, Kukla M, Ludovici D, Andries K, de Béthune MP, Pauwels R, Das K, Clark AD, Frenkel YV, Hughes SH, Medaer B, De Knaep F, Bohets H, De Clerck F, Lampo A, Williams P, Stoffels P.
Abstract : Ideally, an anti-HIV drug should (1) be highly active against wild-type and mutant HIV without allowing breakthrough; (2) have high oral bioavailability and long elimination half-life, allowing once-daily oral treatment at low doses; (3) have minimal adverse effects; and (4) be easy to synthesize and formulate. R278474, a new diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitor (NNRTI), appears to meet these criteria and to be suitable for high compliance oral treatment of HIV-1 infection. The discovery of R278474 was the result of a coordinated multidisciplinary effort involving medicinal chemists, virologists, crystallographers, molecular modelers, toxicologists, analytical chemists, pharmacists, and many others.
|
Effective concentration against human immunodeficiency virus type 1 mutated at 100I
|
Human immunodeficiency virus 1
|
0.4
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of novel diarylpyrimidine analogues and their antiviral activity against human immunodeficiency virus type 1.
Year : 2005
Volume : 48
Issue : 6
First Page : 2072
Last Page : 2079
Authors : Guillemont J, Pasquier E, Palandjian P, Vernier D, Gaurrand S, Lewi PJ, Heeres J, de Jonge MR, Koymans LM, Daeyaert FF, Vinkers MH, Arnold E, Das K, Pauwels R, Andries K, de Béthune MP, Bettens E, Hertogs K, Wigerinck P, Timmerman P, Janssen PA.
Abstract : This paper reports the synthesis and the antiviral properties of new diarylpyrimidine (DAPY) compounds as nonnucleoside reverse transcriptase inhibitors (NNRTIs). The synthesis program around this new DAPY series was further optimized to produce compounds displaying improved activity against a panel of eight clinically relevant single and double mutant strains of human immunodeficiency virus type 1 (HIV-1).
|
Effective concentration against human immunodeficiency virus type 1 mutated at 103N
|
Human immunodeficiency virus 1
|
0.3
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of novel diarylpyrimidine analogues and their antiviral activity against human immunodeficiency virus type 1.
Year : 2005
Volume : 48
Issue : 6
First Page : 2072
Last Page : 2079
Authors : Guillemont J, Pasquier E, Palandjian P, Vernier D, Gaurrand S, Lewi PJ, Heeres J, de Jonge MR, Koymans LM, Daeyaert FF, Vinkers MH, Arnold E, Das K, Pauwels R, Andries K, de Béthune MP, Bettens E, Hertogs K, Wigerinck P, Timmerman P, Janssen PA.
Abstract : This paper reports the synthesis and the antiviral properties of new diarylpyrimidine (DAPY) compounds as nonnucleoside reverse transcriptase inhibitors (NNRTIs). The synthesis program around this new DAPY series was further optimized to produce compounds displaying improved activity against a panel of eight clinically relevant single and double mutant strains of human immunodeficiency virus type 1 (HIV-1).
|
Effective concentration against human immunodeficiency virus type 1 mutated at 181C
|
Human immunodeficiency virus 1
|
1.26
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of novel diarylpyrimidine analogues and their antiviral activity against human immunodeficiency virus type 1.
Year : 2005
Volume : 48
Issue : 6
First Page : 2072
Last Page : 2079
Authors : Guillemont J, Pasquier E, Palandjian P, Vernier D, Gaurrand S, Lewi PJ, Heeres J, de Jonge MR, Koymans LM, Daeyaert FF, Vinkers MH, Arnold E, Das K, Pauwels R, Andries K, de Béthune MP, Bettens E, Hertogs K, Wigerinck P, Timmerman P, Janssen PA.
Abstract : This paper reports the synthesis and the antiviral properties of new diarylpyrimidine (DAPY) compounds as nonnucleoside reverse transcriptase inhibitors (NNRTIs). The synthesis program around this new DAPY series was further optimized to produce compounds displaying improved activity against a panel of eight clinically relevant single and double mutant strains of human immunodeficiency virus type 1 (HIV-1).
|
Effective concentration against human immunodeficiency virus type 1 mutated at 188L
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of novel diarylpyrimidine analogues and their antiviral activity against human immunodeficiency virus type 1.
Year : 2005
Volume : 48
Issue : 6
First Page : 2072
Last Page : 2079
Authors : Guillemont J, Pasquier E, Palandjian P, Vernier D, Gaurrand S, Lewi PJ, Heeres J, de Jonge MR, Koymans LM, Daeyaert FF, Vinkers MH, Arnold E, Das K, Pauwels R, Andries K, de Béthune MP, Bettens E, Hertogs K, Wigerinck P, Timmerman P, Janssen PA.
Abstract : This paper reports the synthesis and the antiviral properties of new diarylpyrimidine (DAPY) compounds as nonnucleoside reverse transcriptase inhibitors (NNRTIs). The synthesis program around this new DAPY series was further optimized to produce compounds displaying improved activity against a panel of eight clinically relevant single and double mutant strains of human immunodeficiency virus type 1 (HIV-1).
|
Effective concentration against human immunodeficiency virus type 1 mutated at 227C
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of novel diarylpyrimidine analogues and their antiviral activity against human immunodeficiency virus type 1.
Year : 2005
Volume : 48
Issue : 6
First Page : 2072
Last Page : 2079
Authors : Guillemont J, Pasquier E, Palandjian P, Vernier D, Gaurrand S, Lewi PJ, Heeres J, de Jonge MR, Koymans LM, Daeyaert FF, Vinkers MH, Arnold E, Das K, Pauwels R, Andries K, de Béthune MP, Bettens E, Hertogs K, Wigerinck P, Timmerman P, Janssen PA.
Abstract : This paper reports the synthesis and the antiviral properties of new diarylpyrimidine (DAPY) compounds as nonnucleoside reverse transcriptase inhibitors (NNRTIs). The synthesis program around this new DAPY series was further optimized to produce compounds displaying improved activity against a panel of eight clinically relevant single and double mutant strains of human immunodeficiency virus type 1 (HIV-1).
|
Effective concentration against human immunodeficiency virus type 1 mutated at 100I+103N
|
Human immunodeficiency virus 1
|
7.95
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of novel diarylpyrimidine analogues and their antiviral activity against human immunodeficiency virus type 1.
Year : 2005
Volume : 48
Issue : 6
First Page : 2072
Last Page : 2079
Authors : Guillemont J, Pasquier E, Palandjian P, Vernier D, Gaurrand S, Lewi PJ, Heeres J, de Jonge MR, Koymans LM, Daeyaert FF, Vinkers MH, Arnold E, Das K, Pauwels R, Andries K, de Béthune MP, Bettens E, Hertogs K, Wigerinck P, Timmerman P, Janssen PA.
Abstract : This paper reports the synthesis and the antiviral properties of new diarylpyrimidine (DAPY) compounds as nonnucleoside reverse transcriptase inhibitors (NNRTIs). The synthesis program around this new DAPY series was further optimized to produce compounds displaying improved activity against a panel of eight clinically relevant single and double mutant strains of human immunodeficiency virus type 1 (HIV-1).
|
Effective concentration against human immunodeficiency virus type 1 mutated at 103N+181C
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of novel diarylpyrimidine analogues and their antiviral activity against human immunodeficiency virus type 1.
Year : 2005
Volume : 48
Issue : 6
First Page : 2072
Last Page : 2079
Authors : Guillemont J, Pasquier E, Palandjian P, Vernier D, Gaurrand S, Lewi PJ, Heeres J, de Jonge MR, Koymans LM, Daeyaert FF, Vinkers MH, Arnold E, Das K, Pauwels R, Andries K, de Béthune MP, Bettens E, Hertogs K, Wigerinck P, Timmerman P, Janssen PA.
Abstract : This paper reports the synthesis and the antiviral properties of new diarylpyrimidine (DAPY) compounds as nonnucleoside reverse transcriptase inhibitors (NNRTIs). The synthesis program around this new DAPY series was further optimized to produce compounds displaying improved activity against a panel of eight clinically relevant single and double mutant strains of human immunodeficiency virus type 1 (HIV-1).
|
Effective concentration against human immunodeficiency virus type 1 mutated at 227L+106A
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of novel diarylpyrimidine analogues and their antiviral activity against human immunodeficiency virus type 1.
Year : 2005
Volume : 48
Issue : 6
First Page : 2072
Last Page : 2079
Authors : Guillemont J, Pasquier E, Palandjian P, Vernier D, Gaurrand S, Lewi PJ, Heeres J, de Jonge MR, Koymans LM, Daeyaert FF, Vinkers MH, Arnold E, Das K, Pauwels R, Andries K, de Béthune MP, Bettens E, Hertogs K, Wigerinck P, Timmerman P, Janssen PA.
Abstract : This paper reports the synthesis and the antiviral properties of new diarylpyrimidine (DAPY) compounds as nonnucleoside reverse transcriptase inhibitors (NNRTIs). The synthesis program around this new DAPY series was further optimized to produce compounds displaying improved activity against a panel of eight clinically relevant single and double mutant strains of human immunodeficiency virus type 1 (HIV-1).
|
Effective concentration for the inhibition of wild type human immunodeficiency virus type 1 LAI strain
|
Human immunodeficiency virus 1
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of novel diarylpyrimidine analogues and their antiviral activity against human immunodeficiency virus type 1.
Year : 2005
Volume : 48
Issue : 6
First Page : 2072
Last Page : 2079
Authors : Guillemont J, Pasquier E, Palandjian P, Vernier D, Gaurrand S, Lewi PJ, Heeres J, de Jonge MR, Koymans LM, Daeyaert FF, Vinkers MH, Arnold E, Das K, Pauwels R, Andries K, de Béthune MP, Bettens E, Hertogs K, Wigerinck P, Timmerman P, Janssen PA.
Abstract : This paper reports the synthesis and the antiviral properties of new diarylpyrimidine (DAPY) compounds as nonnucleoside reverse transcriptase inhibitors (NNRTIs). The synthesis program around this new DAPY series was further optimized to produce compounds displaying improved activity against a panel of eight clinically relevant single and double mutant strains of human immunodeficiency virus type 1 (HIV-1).
|
Antiviral activity against wild type HIV1 LAI infected in MT4 cells by EGFP based replication assay
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis of novel diarylpyrimidine analogues of TMC278 and their antiviral activity against HIV-1 wild-type and mutant strains.
Year : 2007
Volume : 42
Issue : 5
First Page : 567
Last Page : 579
Authors : Mordant C, Schmitt B, Pasquier E, Demestre C, Queguiner L, Masungi C, Peeters A, Smeulders L, Bettens E, Hertogs K, Heeres J, Lewi P, Guillemont J.
Abstract : Novel diarylpyrimidines (DAPY), which represent next generation of non-nucleoside reverse transcriptase inhibitors (NNRTIs), were synthesized and their activities against human immunodeficiency virus type I (HIV-1) assessed. Modulations at positions 2 and 6 of the left phenyl ring generated interesting derivatives of TMC278 displaying high potency against wild-type and mutant viruses compared to nevirapine and efavirenz. The pharmacokinetic profile of the best newly synthesized DAPY was evaluated and compared with TMC278 now in phase II clinical trials.
|
Antiviral activity against HIV1 LAI with RT L100I mutation in MT4 cells by EGFP based replication assay
|
Human immunodeficiency virus 1
|
0.5
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis of novel diarylpyrimidine analogues of TMC278 and their antiviral activity against HIV-1 wild-type and mutant strains.
Year : 2007
Volume : 42
Issue : 5
First Page : 567
Last Page : 579
Authors : Mordant C, Schmitt B, Pasquier E, Demestre C, Queguiner L, Masungi C, Peeters A, Smeulders L, Bettens E, Hertogs K, Heeres J, Lewi P, Guillemont J.
Abstract : Novel diarylpyrimidines (DAPY), which represent next generation of non-nucleoside reverse transcriptase inhibitors (NNRTIs), were synthesized and their activities against human immunodeficiency virus type I (HIV-1) assessed. Modulations at positions 2 and 6 of the left phenyl ring generated interesting derivatives of TMC278 displaying high potency against wild-type and mutant viruses compared to nevirapine and efavirenz. The pharmacokinetic profile of the best newly synthesized DAPY was evaluated and compared with TMC278 now in phase II clinical trials.
|
Antiviral activity against HIV1 LAI with RT Y188L mutation in MT4 cells by EGFP based replication assay
|
Human immunodeficiency virus 1
|
1.2
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis of novel diarylpyrimidine analogues of TMC278 and their antiviral activity against HIV-1 wild-type and mutant strains.
Year : 2007
Volume : 42
Issue : 5
First Page : 567
Last Page : 579
Authors : Mordant C, Schmitt B, Pasquier E, Demestre C, Queguiner L, Masungi C, Peeters A, Smeulders L, Bettens E, Hertogs K, Heeres J, Lewi P, Guillemont J.
Abstract : Novel diarylpyrimidines (DAPY), which represent next generation of non-nucleoside reverse transcriptase inhibitors (NNRTIs), were synthesized and their activities against human immunodeficiency virus type I (HIV-1) assessed. Modulations at positions 2 and 6 of the left phenyl ring generated interesting derivatives of TMC278 displaying high potency against wild-type and mutant viruses compared to nevirapine and efavirenz. The pharmacokinetic profile of the best newly synthesized DAPY was evaluated and compared with TMC278 now in phase II clinical trials.
|
Antiviral activity against HIV1 LAI with RT K103N mutation in MT4 cells by EGFP based replication assay
|
Human immunodeficiency virus 1
|
0.1
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis of novel diarylpyrimidine analogues of TMC278 and their antiviral activity against HIV-1 wild-type and mutant strains.
Year : 2007
Volume : 42
Issue : 5
First Page : 567
Last Page : 579
Authors : Mordant C, Schmitt B, Pasquier E, Demestre C, Queguiner L, Masungi C, Peeters A, Smeulders L, Bettens E, Hertogs K, Heeres J, Lewi P, Guillemont J.
Abstract : Novel diarylpyrimidines (DAPY), which represent next generation of non-nucleoside reverse transcriptase inhibitors (NNRTIs), were synthesized and their activities against human immunodeficiency virus type I (HIV-1) assessed. Modulations at positions 2 and 6 of the left phenyl ring generated interesting derivatives of TMC278 displaying high potency against wild-type and mutant viruses compared to nevirapine and efavirenz. The pharmacokinetic profile of the best newly synthesized DAPY was evaluated and compared with TMC278 now in phase II clinical trials.
|
Antiviral activity against HIV1 LAI with RT Y181C mutation in MT4 cells by EGFP based replication assay
|
Human immunodeficiency virus 1
|
1.3
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis of novel diarylpyrimidine analogues of TMC278 and their antiviral activity against HIV-1 wild-type and mutant strains.
Year : 2007
Volume : 42
Issue : 5
First Page : 567
Last Page : 579
Authors : Mordant C, Schmitt B, Pasquier E, Demestre C, Queguiner L, Masungi C, Peeters A, Smeulders L, Bettens E, Hertogs K, Heeres J, Lewi P, Guillemont J.
Abstract : Novel diarylpyrimidines (DAPY), which represent next generation of non-nucleoside reverse transcriptase inhibitors (NNRTIs), were synthesized and their activities against human immunodeficiency virus type I (HIV-1) assessed. Modulations at positions 2 and 6 of the left phenyl ring generated interesting derivatives of TMC278 displaying high potency against wild-type and mutant viruses compared to nevirapine and efavirenz. The pharmacokinetic profile of the best newly synthesized DAPY was evaluated and compared with TMC278 now in phase II clinical trials.
|
Antiviral activity against HIV1 LAI with RT F227C mutation in MT4 cells by EGFP based replication assay
|
Human immunodeficiency virus 1
|
0.5
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis of novel diarylpyrimidine analogues of TMC278 and their antiviral activity against HIV-1 wild-type and mutant strains.
Year : 2007
Volume : 42
Issue : 5
First Page : 567
Last Page : 579
Authors : Mordant C, Schmitt B, Pasquier E, Demestre C, Queguiner L, Masungi C, Peeters A, Smeulders L, Bettens E, Hertogs K, Heeres J, Lewi P, Guillemont J.
Abstract : Novel diarylpyrimidines (DAPY), which represent next generation of non-nucleoside reverse transcriptase inhibitors (NNRTIs), were synthesized and their activities against human immunodeficiency virus type I (HIV-1) assessed. Modulations at positions 2 and 6 of the left phenyl ring generated interesting derivatives of TMC278 displaying high potency against wild-type and mutant viruses compared to nevirapine and efavirenz. The pharmacokinetic profile of the best newly synthesized DAPY was evaluated and compared with TMC278 now in phase II clinical trials.
|
Antiviral activity against HIV1 LAI with RT L100I and K103N mutation in MT4 cells by EGFP based replication assay
|
Human immunodeficiency virus 1
|
7.5
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis of novel diarylpyrimidine analogues of TMC278 and their antiviral activity against HIV-1 wild-type and mutant strains.
Year : 2007
Volume : 42
Issue : 5
First Page : 567
Last Page : 579
Authors : Mordant C, Schmitt B, Pasquier E, Demestre C, Queguiner L, Masungi C, Peeters A, Smeulders L, Bettens E, Hertogs K, Heeres J, Lewi P, Guillemont J.
Abstract : Novel diarylpyrimidines (DAPY), which represent next generation of non-nucleoside reverse transcriptase inhibitors (NNRTIs), were synthesized and their activities against human immunodeficiency virus type I (HIV-1) assessed. Modulations at positions 2 and 6 of the left phenyl ring generated interesting derivatives of TMC278 displaying high potency against wild-type and mutant viruses compared to nevirapine and efavirenz. The pharmacokinetic profile of the best newly synthesized DAPY was evaluated and compared with TMC278 now in phase II clinical trials.
|
Antiviral activity against HIV1 LAI with RT K103N and Y181C mutation in MT4 cells by EGFP based replication assay
|
Human immunodeficiency virus 1
|
3.2
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis of novel diarylpyrimidine analogues of TMC278 and their antiviral activity against HIV-1 wild-type and mutant strains.
Year : 2007
Volume : 42
Issue : 5
First Page : 567
Last Page : 579
Authors : Mordant C, Schmitt B, Pasquier E, Demestre C, Queguiner L, Masungi C, Peeters A, Smeulders L, Bettens E, Hertogs K, Heeres J, Lewi P, Guillemont J.
Abstract : Novel diarylpyrimidines (DAPY), which represent next generation of non-nucleoside reverse transcriptase inhibitors (NNRTIs), were synthesized and their activities against human immunodeficiency virus type I (HIV-1) assessed. Modulations at positions 2 and 6 of the left phenyl ring generated interesting derivatives of TMC278 displaying high potency against wild-type and mutant viruses compared to nevirapine and efavirenz. The pharmacokinetic profile of the best newly synthesized DAPY was evaluated and compared with TMC278 now in phase II clinical trials.
|
Antiviral activity against HIV1 LAI with RT F227C and V106A mutation in MT4 cells by EGFP based replication assay
|
Human immunodeficiency virus 1
|
0.5
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis of novel diarylpyrimidine analogues of TMC278 and their antiviral activity against HIV-1 wild-type and mutant strains.
Year : 2007
Volume : 42
Issue : 5
First Page : 567
Last Page : 579
Authors : Mordant C, Schmitt B, Pasquier E, Demestre C, Queguiner L, Masungi C, Peeters A, Smeulders L, Bettens E, Hertogs K, Heeres J, Lewi P, Guillemont J.
Abstract : Novel diarylpyrimidines (DAPY), which represent next generation of non-nucleoside reverse transcriptase inhibitors (NNRTIs), were synthesized and their activities against human immunodeficiency virus type I (HIV-1) assessed. Modulations at positions 2 and 6 of the left phenyl ring generated interesting derivatives of TMC278 displaying high potency against wild-type and mutant viruses compared to nevirapine and efavirenz. The pharmacokinetic profile of the best newly synthesized DAPY was evaluated and compared with TMC278 now in phase II clinical trials.
|
Antiviral activity against HIV1
|
Human immunodeficiency virus 1
|
0.4
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Unified QSAR approach to antimicrobials. 4. Multi-target QSAR modeling and comparative multi-distance study of the giant components of antiviral drug-drug complex networks.
Year : 2009
Volume : 17
Issue : 2
First Page : 569
Last Page : 575
Authors : Prado-Prado FJ, Martinez de la Vega O, Uriarte E, Ubeira FM, Chou KC, González-Díaz H.
Abstract : One limitation of almost all antiviral Quantitative Structure-Activity Relationships (QSAR) models is that they predict the biological activity of drugs against only one species of virus. Consequently, the development of multi-tasking QSAR models (mt-QSAR) to predict drugs activity against different species of virus is of the major vitally important. These mt-QSARs offer also a good opportunity to construct drug-drug Complex Networks (CNs) that can be used to explore large and complex drug-viral species databases. It is known that in very large CNs we can use the Giant Component (GC) as a representative sub-set of nodes (drugs) and but the drug-drug similarity function selected may strongly determines the final network obtained. In the three previous works of the present series we reported mt-QSAR models to predict the antimicrobial activity against different fungi [Gonzalez-Diaz, H.; Prado-Prado, F. J.; Santana, L.; Uriarte, E. Bioorg.Med.Chem.2006, 14, 5973], bacteria [Prado-Prado, F. J.; Gonzalez-Diaz, H.; Santana, L.; Uriarte E. Bioorg.Med.Chem.2007, 15, 897] or parasite species [Prado-Prado, F.J.; González-Díaz, H.; Martinez de la Vega, O.; Ubeira, F.M.; Chou K.C. Bioorg.Med.Chem.2008, 16, 5871]. However, including these works, we do not found any report of mt-QSAR models for antivirals drug, or a comparative study of the different GC extracted from drug-drug CNs based on different similarity functions. In this work, we used Linear Discriminant Analysis (LDA) to fit a mt-QSAR model that classify 600 drugs as active or non-active against the 41 different tested species of virus. The model correctly classifies 143 of 169 active compounds (specificity=84.62%) and 119 of 139 non-active compounds (sensitivity=85.61%) and presents overall training accuracy of 85.1% (262 of 308 cases). Validation of the model was carried out by means of external predicting series, classifying the model 466 of 514, 90.7% of compounds. In order to illustrate the performance of the model in practice, we develop a virtual screening recognizing the model as active 92.7%, 102 of 110 antivirus compounds. These compounds were never use in training or predicting series. Next, we obtained and compared the topology of the CNs and their respective GCs based on Euclidean, Manhattan, Chebychey, Pearson and other similarity measures. The GC of the Manhattan network showed the more interesting features for drug-drug similarity search. We also give the procedure for the construction of Back-Projection Maps for the contribution of each drug sub-structure to the antiviral activity against different species.
|
Antiviral activity against HIV1 3B infected in human MT4 cells assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
0.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of diarylpyridine derivatives as novel non-nucleoside HIV-1 reverse transcriptase inhibitors.
Year : 2009
Volume : 19
Issue : 18
First Page : 5482
Last Page : 5485
Authors : Tian X, Qin B, Lu H, Lai W, Jiang S, Lee KH, Chen CH, Xie L.
Abstract : Two series (4 and 5) of diarylpyridine derivatives were designed, synthesized, and evaluated for anti-HIV-1 activity. The most promising compound, 5e, inhibited HIV-1 IIIB, NL4-3, and RTMDR1 with low nanomolar EC50 values and selectivity indexes of >10,000. The results of this study indicate that diarylpyridine can be used as a novel scaffold to derive a new class of potent NNRTIs, active against both wild-type and drug-resistant HIV-1 strains.
|
Antimalarial activity against Plasmodium falciparum W2mef at 10 uM after 48 hrs by hoechst 33342-thiazole orange stain based flow cytometry assay
|
Plasmodium falciparum
|
49.75
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Addressing the malaria drug resistance challenge using flow cytometry to discover new antimalarials.
Year : 2009
Volume : 19
Issue : 18
First Page : 5452
Last Page : 5457
Authors : Grimberg BT, Jaworska MM, Hough LB, Zimmerman PA, Phillips JG.
Abstract : A new flow cytometry method that uses an optimized DNA and RNA staining strategy to monitor the growth and development of the Plasmodium falciparum strain W2mef has been used in a pilot study and has identified Bay 43-9006 1, SU 11274 2, and TMC 125 5 as compounds that exhibit potent (<1 microM) overall and ring stage in vitro antimalarial activity.
|
Antiviral activity against Human immunodeficiency virus 1 subtype D isolate 92UG001 infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
0.26
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype D isolate 92UG024 infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
0.38
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype D isolate 92UG035 infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
0.07
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype E isolate 92TH006 infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
0.08
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype E isolate 93TH073 infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
0.07
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype E isolate CMU08 infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
1.01
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype F isolate 93BR019 infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
0.95
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype F isolate 93BR020 infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
0.16
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype F isolate 93BR029 infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
0.19
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype G isolate G3 infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
0.25
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype G isolate JV1083 infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
0.26
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype G isolate RU132 infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
0.51
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype (H) infected in human MT4 cells assessed as reduction in virus induced cytopathicity
|
Human immunodeficiency virus 1
|
0.24
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype G infected in human MT4 cells assessed as reduction in virus induced cytopathicity
|
Human immunodeficiency virus 1
|
0.14
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype D infected in human MT4 cells assessed as reduction in virus induced cytopathicity
|
Human immunodeficiency virus 1
|
0.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype F1 infected in human MT4 cells assessed as reduction in virus induced cytopathicity
|
Human immunodeficiency virus 1
|
0.21
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype C infected in human MT4 cells assessed as reduction in virus induced cytopathicity
|
Human immunodeficiency virus 1
|
0.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype BG infected in human MT4 cells assessed as reduction in virus induced cytopathicity
|
Human immunodeficiency virus 1
|
0.22
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype AG infected in human MT4 cells assessed as reduction in virus induced cytopathicity
|
Human immunodeficiency virus 1
|
0.13
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype AE infected in human MT4 cells assessed as reduction in virus induced cytopathicity
|
Human immunodeficiency virus 1
|
0.21
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype A1 infected in human MT4 cells assessed as reduction in virus induced cytopathicity
|
Human immunodeficiency virus 1
|
0.44
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 3B infected in human MT4 cells assessed as reduction in virus induced cytopathicity
|
Human immunodeficiency virus 1
|
0.73
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype O misolate BCF01 infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
3.13
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype O isolate BCF02 infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
2.88
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype O isolate BCF03 infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
8.45
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Inhibition of HIV1 Reverse transcriptase by primer extension-based scintillation assay
|
Human immunodeficiency virus 1
|
42.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype A isolate 92UG029 infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
0.44
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype B isolate 93BR021 infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
0.23
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype A isolate 92UG037 infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
0.24
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype A isolate 92RW020 infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
0.07
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype B isolate JR-CSF infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
0.51
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype B isolate WEJO infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
0.08
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype C isolate 92BR025 infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
0.33
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype C isolate 93IN101 infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
0.53
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 subtype C isolate 93MW959 infected in human PBMC cells by cell based assay
|
Human immunodeficiency virus 1
|
0.11
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1.
Year : 2010
Volume : 54
Issue : 2
First Page : 718
Last Page : 727
Authors : Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT.
Abstract : Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
|
Antiviral activity against Human immunodeficiency virus 1 NL4.3 infected in human MT2 cells assessed as inhibition of viral infection
|
Human immunodeficiency virus 1
|
0.67
nM
|
|
Journal : J. Med. Chem.
Title : Computationally-guided optimization of a docking hit to yield catechol diethers as potent anti-HIV agents.
Year : 2011
Volume : 54
Issue : 24
First Page : 8582
Last Page : 8591
Authors : Bollini M, Domaoal RA, Thakur VV, Gallardo-Macias R, Spasov KA, Anderson KS, Jorgensen WL.
Abstract : A 5-μM docking hit has been optimized to an extraordinarily potent (55 pM) non-nucleoside inhibitor of HIV reverse transcriptase. Use of free energy perturbation (FEP) calculations to predict relative free energies of binding aided the optimizations by identifying optimal substitution patterns for phenyl rings and a linker. The most potent resultant catechol diethers feature terminal uracil and cyanovinylphenyl groups. A halogen bond with Pro95 likely contributes to the extreme potency of compound 42. In addition, several examples are provided illustrating failures of attempted grafting of a substructure from a very active compound onto a seemingly related scaffold to improve its activity.
|
Antiviral activity against Human immunodeficiency virus 1 NL4.3 reverse transcriptase Y181C mutant infected in human MT2 cells assessed as inhibition of viral infection
|
Human immunodeficiency virus 1
|
0.65
nM
|
|
Journal : J. Med. Chem.
Title : Computationally-guided optimization of a docking hit to yield catechol diethers as potent anti-HIV agents.
Year : 2011
Volume : 54
Issue : 24
First Page : 8582
Last Page : 8591
Authors : Bollini M, Domaoal RA, Thakur VV, Gallardo-Macias R, Spasov KA, Anderson KS, Jorgensen WL.
Abstract : A 5-μM docking hit has been optimized to an extraordinarily potent (55 pM) non-nucleoside inhibitor of HIV reverse transcriptase. Use of free energy perturbation (FEP) calculations to predict relative free energies of binding aided the optimizations by identifying optimal substitution patterns for phenyl rings and a linker. The most potent resultant catechol diethers feature terminal uracil and cyanovinylphenyl groups. A halogen bond with Pro95 likely contributes to the extreme potency of compound 42. In addition, several examples are provided illustrating failures of attempted grafting of a substructure from a very active compound onto a seemingly related scaffold to improve its activity.
|
Antiviral activity against Human immunodeficiency virus 1 NL4.3 reverse transcriptase K103N and Y181C double mutant infected in human MT2 cells assessed as inhibition of viral infection
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Computationally-guided optimization of a docking hit to yield catechol diethers as potent anti-HIV agents.
Year : 2011
Volume : 54
Issue : 24
First Page : 8582
Last Page : 8591
Authors : Bollini M, Domaoal RA, Thakur VV, Gallardo-Macias R, Spasov KA, Anderson KS, Jorgensen WL.
Abstract : A 5-μM docking hit has been optimized to an extraordinarily potent (55 pM) non-nucleoside inhibitor of HIV reverse transcriptase. Use of free energy perturbation (FEP) calculations to predict relative free energies of binding aided the optimizations by identifying optimal substitution patterns for phenyl rings and a linker. The most potent resultant catechol diethers feature terminal uracil and cyanovinylphenyl groups. A halogen bond with Pro95 likely contributes to the extreme potency of compound 42. In addition, several examples are provided illustrating failures of attempted grafting of a substructure from a very active compound onto a seemingly related scaffold to improve its activity.
|
Antiviral activity against Human immunodeficiency virus 1 NL4.3 infected in human MT4 cells assessed as inhibition of viral infection
|
Human immunodeficiency virus 1
|
0.4
nM
|
|
Journal : J. Med. Chem.
Title : Computationally-guided optimization of a docking hit to yield catechol diethers as potent anti-HIV agents.
Year : 2011
Volume : 54
Issue : 24
First Page : 8582
Last Page : 8591
Authors : Bollini M, Domaoal RA, Thakur VV, Gallardo-Macias R, Spasov KA, Anderson KS, Jorgensen WL.
Abstract : A 5-μM docking hit has been optimized to an extraordinarily potent (55 pM) non-nucleoside inhibitor of HIV reverse transcriptase. Use of free energy perturbation (FEP) calculations to predict relative free energies of binding aided the optimizations by identifying optimal substitution patterns for phenyl rings and a linker. The most potent resultant catechol diethers feature terminal uracil and cyanovinylphenyl groups. A halogen bond with Pro95 likely contributes to the extreme potency of compound 42. In addition, several examples are provided illustrating failures of attempted grafting of a substructure from a very active compound onto a seemingly related scaffold to improve its activity.
|
Antiviral activity against Human immunodeficiency virus 1 NL4.3 reverse transcriptase Y181C mutant infected in human MT4 cells assessed as inhibition of viral infection
|
Human immunodeficiency virus 1
|
1.3
nM
|
|
Journal : J. Med. Chem.
Title : Computationally-guided optimization of a docking hit to yield catechol diethers as potent anti-HIV agents.
Year : 2011
Volume : 54
Issue : 24
First Page : 8582
Last Page : 8591
Authors : Bollini M, Domaoal RA, Thakur VV, Gallardo-Macias R, Spasov KA, Anderson KS, Jorgensen WL.
Abstract : A 5-μM docking hit has been optimized to an extraordinarily potent (55 pM) non-nucleoside inhibitor of HIV reverse transcriptase. Use of free energy perturbation (FEP) calculations to predict relative free energies of binding aided the optimizations by identifying optimal substitution patterns for phenyl rings and a linker. The most potent resultant catechol diethers feature terminal uracil and cyanovinylphenyl groups. A halogen bond with Pro95 likely contributes to the extreme potency of compound 42. In addition, several examples are provided illustrating failures of attempted grafting of a substructure from a very active compound onto a seemingly related scaffold to improve its activity.
|
Antiviral activity against Human immunodeficiency virus 1 NL4.3 reverse transcriptase K103N and Y181C double mutant infected in human MT4 cells assessed as inhibition of viral infection
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Computationally-guided optimization of a docking hit to yield catechol diethers as potent anti-HIV agents.
Year : 2011
Volume : 54
Issue : 24
First Page : 8582
Last Page : 8591
Authors : Bollini M, Domaoal RA, Thakur VV, Gallardo-Macias R, Spasov KA, Anderson KS, Jorgensen WL.
Abstract : A 5-μM docking hit has been optimized to an extraordinarily potent (55 pM) non-nucleoside inhibitor of HIV reverse transcriptase. Use of free energy perturbation (FEP) calculations to predict relative free energies of binding aided the optimizations by identifying optimal substitution patterns for phenyl rings and a linker. The most potent resultant catechol diethers feature terminal uracil and cyanovinylphenyl groups. A halogen bond with Pro95 likely contributes to the extreme potency of compound 42. In addition, several examples are provided illustrating failures of attempted grafting of a substructure from a very active compound onto a seemingly related scaffold to improve its activity.
|
Antiviral activity against Human immunodeficiency virus 1 NL4-3 infected in human TZM-bl cells assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
0.52
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of 2,4-diarylanilines as non-nucleoside HIV-1 reverse transcriptase inhibitors.
Year : 2012
Volume : 22
Issue : 7
First Page : 2376
Last Page : 2379
Authors : Sun LQ, Qin B, Huang L, Qian K, Chen CH, Lee KH, Xie L.
Abstract : The current optimization of 2,4-diarylaniline analogs (DAANs) on the central phenyl ring provided a series of new active DAAN derivatives 9a-9e, indicating an accessible modification approach that could improve anti-HIV potency against wild-type and resistant strains, aqueous solubility, and metabolic stability. A new compound 9e not only exhibited extremely high potency against wild-type virus (EC(50) 0.53 nM) and several resistant viral strains (EC(50) 0.36-3.9 nM), but also showed desirable aqueous solubility and metabolic stability, which were comparable or better than those of the anti-HIV-1 drug TMC278 (2). Thus, new compound 9e might be a potential drug candidate for further development of novel next-generation NNRTIs.
|
Antiviral activity against multi-reverse transcriptase-resistant Human immunodeficiency virus 1
|
Human immunodeficiency virus 1
|
0.49
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of 2,4-diarylanilines as non-nucleoside HIV-1 reverse transcriptase inhibitors.
Year : 2012
Volume : 22
Issue : 7
First Page : 2376
Last Page : 2379
Authors : Sun LQ, Qin B, Huang L, Qian K, Chen CH, Lee KH, Xie L.
Abstract : The current optimization of 2,4-diarylaniline analogs (DAANs) on the central phenyl ring provided a series of new active DAAN derivatives 9a-9e, indicating an accessible modification approach that could improve anti-HIV potency against wild-type and resistant strains, aqueous solubility, and metabolic stability. A new compound 9e not only exhibited extremely high potency against wild-type virus (EC(50) 0.53 nM) and several resistant viral strains (EC(50) 0.36-3.9 nM), but also showed desirable aqueous solubility and metabolic stability, which were comparable or better than those of the anti-HIV-1 drug TMC278 (2). Thus, new compound 9e might be a potential drug candidate for further development of novel next-generation NNRTIs.
|
Antiviral activity against Human immunodeficiency virus 1 harboring reverse transcriptase K101E mutant
|
Human immunodeficiency virus 1
|
5.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of 2,4-diarylanilines as non-nucleoside HIV-1 reverse transcriptase inhibitors.
Year : 2012
Volume : 22
Issue : 7
First Page : 2376
Last Page : 2379
Authors : Sun LQ, Qin B, Huang L, Qian K, Chen CH, Lee KH, Xie L.
Abstract : The current optimization of 2,4-diarylaniline analogs (DAANs) on the central phenyl ring provided a series of new active DAAN derivatives 9a-9e, indicating an accessible modification approach that could improve anti-HIV potency against wild-type and resistant strains, aqueous solubility, and metabolic stability. A new compound 9e not only exhibited extremely high potency against wild-type virus (EC(50) 0.53 nM) and several resistant viral strains (EC(50) 0.36-3.9 nM), but also showed desirable aqueous solubility and metabolic stability, which were comparable or better than those of the anti-HIV-1 drug TMC278 (2). Thus, new compound 9e might be a potential drug candidate for further development of novel next-generation NNRTIs.
|
Antiviral activity against Human immunodeficiency virus 1 harboring reverse transcriptase E138K mutant
|
Human immunodeficiency virus 1
|
5.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of 2,4-diarylanilines as non-nucleoside HIV-1 reverse transcriptase inhibitors.
Year : 2012
Volume : 22
Issue : 7
First Page : 2376
Last Page : 2379
Authors : Sun LQ, Qin B, Huang L, Qian K, Chen CH, Lee KH, Xie L.
Abstract : The current optimization of 2,4-diarylaniline analogs (DAANs) on the central phenyl ring provided a series of new active DAAN derivatives 9a-9e, indicating an accessible modification approach that could improve anti-HIV potency against wild-type and resistant strains, aqueous solubility, and metabolic stability. A new compound 9e not only exhibited extremely high potency against wild-type virus (EC(50) 0.53 nM) and several resistant viral strains (EC(50) 0.36-3.9 nM), but also showed desirable aqueous solubility and metabolic stability, which were comparable or better than those of the anti-HIV-1 drug TMC278 (2). Thus, new compound 9e might be a potential drug candidate for further development of novel next-generation NNRTIs.
|
Antiviral activity against wild type HIV1 NL4-3 infected in human MT4 cells assessed as reduction of viral p24 level cells by fluorescence assay relative to wild type HIV1 NL4-3 after 4 days by ELISA
|
Human immunodeficiency virus 1
|
0.55
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of betulinic acid derivatives as entry inhibitors against HIV-1 and bevirimat-resistant HIV-1 variants.
Year : 2012
Volume : 22
Issue : 16
First Page : 5190
Last Page : 5194
Authors : Dang Z, Qian K, Ho P, Zhu L, Lee KH, Huang L, Chen CH.
Abstract : Betulinic acid derivatives modified at the C28 position are HIV-1entry inhibitors such as compound A43D; however, modified at the C3 position instead of C28 give HIV-1 maturation inhibitor such as bevirimat. Bevirimat exhibited promising pharmacokinetic profiles in clinical trials, but its effectiveness was compromised by the high baseline drug resistance of HIV-1 variants with polymorphism in the putative drug binding site. In an effort to determine whether the viruses with bevirimat resistant polymorphism also altered their sensitivities to the betulinic acid derivatives that inhibit HIV-1 entry, a series of new betulinic acid entry inhibitors were synthesized and tested for their activities against HIV-1 NL4-3 and NL4-3 variants resistant to bevirimat. The results show that the bevirimat resistant viruses were approximately 5- to10-fold more sensitive to three new glutamine ester derivatives (13, 15 and 38) and A43D in an HIV-1 multi-cycle replication assay. In contrast, the wild type NL4-3 and the bevirimat resistant variants were equally sensitive to the HIV-1 RT inhibitor AZT. In addition, these three new compounds markedly improved microsomal stability compared to A43D.
|
Antiviral activity against bevirimat-resistant HIV1 NL4-3 harboring QVT motif of Gag SP1 V370A mutant infected in human MT4 cells assessed as reduction of viral p24 level cells by fluorescence assay relative to wild type HIV1 NL4-3 after 4 days by ELISA
|
Human immunodeficiency virus 1
|
0.52
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of betulinic acid derivatives as entry inhibitors against HIV-1 and bevirimat-resistant HIV-1 variants.
Year : 2012
Volume : 22
Issue : 16
First Page : 5190
Last Page : 5194
Authors : Dang Z, Qian K, Ho P, Zhu L, Lee KH, Huang L, Chen CH.
Abstract : Betulinic acid derivatives modified at the C28 position are HIV-1entry inhibitors such as compound A43D; however, modified at the C3 position instead of C28 give HIV-1 maturation inhibitor such as bevirimat. Bevirimat exhibited promising pharmacokinetic profiles in clinical trials, but its effectiveness was compromised by the high baseline drug resistance of HIV-1 variants with polymorphism in the putative drug binding site. In an effort to determine whether the viruses with bevirimat resistant polymorphism also altered their sensitivities to the betulinic acid derivatives that inhibit HIV-1 entry, a series of new betulinic acid entry inhibitors were synthesized and tested for their activities against HIV-1 NL4-3 and NL4-3 variants resistant to bevirimat. The results show that the bevirimat resistant viruses were approximately 5- to10-fold more sensitive to three new glutamine ester derivatives (13, 15 and 38) and A43D in an HIV-1 multi-cycle replication assay. In contrast, the wild type NL4-3 and the bevirimat resistant variants were equally sensitive to the HIV-1 RT inhibitor AZT. In addition, these three new compounds markedly improved microsomal stability compared to A43D.
|
Antiviral activity against HIV-1 harboring reverse transcriptase E138K mutant infected in human TZM-bl cells assessed as inhibition of viral replication after 2 days by luciferase reporter gene based luminescence assay
|
Human immunodeficiency virus 1
|
5.2
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and preclinical evaluations of novel 4-substituted 1,5-diarylanilines as potent HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) drug candidates.
Year : 2012
Volume : 55
Issue : 16
First Page : 7219
Last Page : 7229
Authors : Sun LQ, Zhu L, Qian K, Qin B, Huang L, Chen CH, Lee KH, Xie L.
Abstract : Twenty-one new 4-substituted diarylaniline compounds (DAANs) (series 13, 14, and 15) were designed, synthesized, and evaluated against wild-type and drug resistant HIV-1 viral strains. As a result, approximately a dozen new DAANs showed high potency with low nano- to subnanomolar EC(50) values ranging from 0.2 to 10 nM. The three most promising compounds 14e, 14h, and 15h exhibited high potency against wild-type and drug-resistant viral strains with EC(50) values at the subnanomolar level (0.29-0.87 nM) and were comparable to or more potent than the new NNRTI drug riplivirine (2) in the same assays. Druglike physicochemical property assessments revealed that the most active DAANs (EC(50) < 10 nM) have better aqueous solubility (>1-90 μg/mL at pH 7.4 and pH 2) and metabolic stability in vitro than 2, as well as desirable log P values (<5) and polar surface areas (PSA) (<140 Å(2)). These promising results warrant further development of this novel compound class as potential potent anti-AIDS clinical trial candidates.
|
Antiviral activity against multidrug-resistant HIV-1 RTMDR infected in human TZM-bl cells assessed as inhibition of viral replication after 2 days by luciferase reporter gene based luminescence assay
|
Human immunodeficiency virus 1
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and preclinical evaluations of novel 4-substituted 1,5-diarylanilines as potent HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) drug candidates.
Year : 2012
Volume : 55
Issue : 16
First Page : 7219
Last Page : 7229
Authors : Sun LQ, Zhu L, Qian K, Qin B, Huang L, Chen CH, Lee KH, Xie L.
Abstract : Twenty-one new 4-substituted diarylaniline compounds (DAANs) (series 13, 14, and 15) were designed, synthesized, and evaluated against wild-type and drug resistant HIV-1 viral strains. As a result, approximately a dozen new DAANs showed high potency with low nano- to subnanomolar EC(50) values ranging from 0.2 to 10 nM. The three most promising compounds 14e, 14h, and 15h exhibited high potency against wild-type and drug-resistant viral strains with EC(50) values at the subnanomolar level (0.29-0.87 nM) and were comparable to or more potent than the new NNRTI drug riplivirine (2) in the same assays. Druglike physicochemical property assessments revealed that the most active DAANs (EC(50) < 10 nM) have better aqueous solubility (>1-90 μg/mL at pH 7.4 and pH 2) and metabolic stability in vitro than 2, as well as desirable log P values (<5) and polar surface areas (PSA) (<140 Å(2)). These promising results warrant further development of this novel compound class as potential potent anti-AIDS clinical trial candidates.
|
Antiviral activity against HIV-1 harboring reverse transcriptase K101E mutant infected in human TZM-bl cells assessed as inhibition of viral replication after 2 days by luciferase reporter gene based luminescence assay
|
Human immunodeficiency virus 1
|
5.7
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and preclinical evaluations of novel 4-substituted 1,5-diarylanilines as potent HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) drug candidates.
Year : 2012
Volume : 55
Issue : 16
First Page : 7219
Last Page : 7229
Authors : Sun LQ, Zhu L, Qian K, Qin B, Huang L, Chen CH, Lee KH, Xie L.
Abstract : Twenty-one new 4-substituted diarylaniline compounds (DAANs) (series 13, 14, and 15) were designed, synthesized, and evaluated against wild-type and drug resistant HIV-1 viral strains. As a result, approximately a dozen new DAANs showed high potency with low nano- to subnanomolar EC(50) values ranging from 0.2 to 10 nM. The three most promising compounds 14e, 14h, and 15h exhibited high potency against wild-type and drug-resistant viral strains with EC(50) values at the subnanomolar level (0.29-0.87 nM) and were comparable to or more potent than the new NNRTI drug riplivirine (2) in the same assays. Druglike physicochemical property assessments revealed that the most active DAANs (EC(50) < 10 nM) have better aqueous solubility (>1-90 μg/mL at pH 7.4 and pH 2) and metabolic stability in vitro than 2, as well as desirable log P values (<5) and polar surface areas (PSA) (<140 Å(2)). These promising results warrant further development of this novel compound class as potential potent anti-AIDS clinical trial candidates.
|
Antiviral activity against HIV-1 NL4-3 infected in human TZM-bl cells assessed as inhibition of viral replication after 2 days by luciferase reporter gene based luminescence assay
|
Human immunodeficiency virus 1
|
0.52
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and preclinical evaluations of novel 4-substituted 1,5-diarylanilines as potent HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) drug candidates.
Year : 2012
Volume : 55
Issue : 16
First Page : 7219
Last Page : 7229
Authors : Sun LQ, Zhu L, Qian K, Qin B, Huang L, Chen CH, Lee KH, Xie L.
Abstract : Twenty-one new 4-substituted diarylaniline compounds (DAANs) (series 13, 14, and 15) were designed, synthesized, and evaluated against wild-type and drug resistant HIV-1 viral strains. As a result, approximately a dozen new DAANs showed high potency with low nano- to subnanomolar EC(50) values ranging from 0.2 to 10 nM. The three most promising compounds 14e, 14h, and 15h exhibited high potency against wild-type and drug-resistant viral strains with EC(50) values at the subnanomolar level (0.29-0.87 nM) and were comparable to or more potent than the new NNRTI drug riplivirine (2) in the same assays. Druglike physicochemical property assessments revealed that the most active DAANs (EC(50) < 10 nM) have better aqueous solubility (>1-90 μg/mL at pH 7.4 and pH 2) and metabolic stability in vitro than 2, as well as desirable log P values (<5) and polar surface areas (PSA) (<140 Å(2)). These promising results warrant further development of this novel compound class as potential potent anti-AIDS clinical trial candidates.
|
Antiviral activity against NNRTI-resistant HIV1 harboring reverse transcriptase Y188L mutant infected in human MT4 cells assessed as inhibition of viral replication after 72 hrs by HeLa-CD4-LTR-beta-gal assay
|
Human immunodeficiency virus 1
|
3.7
nM
|
|
Journal : J. Med. Chem.
Title : Rational design of potent non-nucleoside inhibitors of HIV-1 reverse transcriptase.
Year : 2012
Volume : 55
Issue : 23
First Page : 10601
Last Page : 10609
Authors : Chong P, Sebahar P, Youngman M, Garrido D, Zhang H, Stewart EL, Nolte RT, Wang L, Ferris RG, Edelstein M, Weaver K, Mathis A, Peat A.
Abstract : A new series of non-nucleoside reverse transcriptase inhibitors based on an imidazole-amide biarylether scaffold has been identified and shown to possess potent antiviral activity against HIV-1, including the NNRTI-resistant Y188L mutated virus. X-ray crystallography of inhibitors bound to reverse transcriptase, including a structure of the Y188L RT protein, was used extensively to help identify and optimize the key hydrogen-bonding motif. This led directly to the design of compound 43 that exhibits remarkable antiviral activity (EC50<1 nM) against a wide range of NNRTI-resistant viruses and a favorable pharmacokinetic profile across multiple species.
|
Antiviral activity against NNRTI-resistant HIV1 harboring reverse transcriptase Y181C mutant infected in human MT4 cells assessed as inhibition of viral replication after 72 hrs by HeLa-CD4-LTR-beta-gal assay
|
Human immunodeficiency virus 1
|
1.3
nM
|
|
Journal : J. Med. Chem.
Title : Rational design of potent non-nucleoside inhibitors of HIV-1 reverse transcriptase.
Year : 2012
Volume : 55
Issue : 23
First Page : 10601
Last Page : 10609
Authors : Chong P, Sebahar P, Youngman M, Garrido D, Zhang H, Stewart EL, Nolte RT, Wang L, Ferris RG, Edelstein M, Weaver K, Mathis A, Peat A.
Abstract : A new series of non-nucleoside reverse transcriptase inhibitors based on an imidazole-amide biarylether scaffold has been identified and shown to possess potent antiviral activity against HIV-1, including the NNRTI-resistant Y188L mutated virus. X-ray crystallography of inhibitors bound to reverse transcriptase, including a structure of the Y188L RT protein, was used extensively to help identify and optimize the key hydrogen-bonding motif. This led directly to the design of compound 43 that exhibits remarkable antiviral activity (EC50<1 nM) against a wide range of NNRTI-resistant viruses and a favorable pharmacokinetic profile across multiple species.
|
Antiviral activity against NNRTI-resistant HIV1 harboring reverse transcriptase K103N mutant infected in human MT4 cells assessed as inhibition of viral replication after 72 hrs by HeLa-CD4-LTR-beta-gal assay
|
Human immunodeficiency virus 1
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Rational design of potent non-nucleoside inhibitors of HIV-1 reverse transcriptase.
Year : 2012
Volume : 55
Issue : 23
First Page : 10601
Last Page : 10609
Authors : Chong P, Sebahar P, Youngman M, Garrido D, Zhang H, Stewart EL, Nolte RT, Wang L, Ferris RG, Edelstein M, Weaver K, Mathis A, Peat A.
Abstract : A new series of non-nucleoside reverse transcriptase inhibitors based on an imidazole-amide biarylether scaffold has been identified and shown to possess potent antiviral activity against HIV-1, including the NNRTI-resistant Y188L mutated virus. X-ray crystallography of inhibitors bound to reverse transcriptase, including a structure of the Y188L RT protein, was used extensively to help identify and optimize the key hydrogen-bonding motif. This led directly to the design of compound 43 that exhibits remarkable antiviral activity (EC50<1 nM) against a wide range of NNRTI-resistant viruses and a favorable pharmacokinetic profile across multiple species.
|
Antiviral activity against HIV1 expressing wild type reverse transcriptase infected in human MT4 cells assessed as inhibition of viral replication after 72 hrs by HeLa-CD4-LTR-beta-gal assay
|
Human immunodeficiency virus 1
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Rational design of potent non-nucleoside inhibitors of HIV-1 reverse transcriptase.
Year : 2012
Volume : 55
Issue : 23
First Page : 10601
Last Page : 10609
Authors : Chong P, Sebahar P, Youngman M, Garrido D, Zhang H, Stewart EL, Nolte RT, Wang L, Ferris RG, Edelstein M, Weaver K, Mathis A, Peat A.
Abstract : A new series of non-nucleoside reverse transcriptase inhibitors based on an imidazole-amide biarylether scaffold has been identified and shown to possess potent antiviral activity against HIV-1, including the NNRTI-resistant Y188L mutated virus. X-ray crystallography of inhibitors bound to reverse transcriptase, including a structure of the Y188L RT protein, was used extensively to help identify and optimize the key hydrogen-bonding motif. This led directly to the design of compound 43 that exhibits remarkable antiviral activity (EC50<1 nM) against a wide range of NNRTI-resistant viruses and a favorable pharmacokinetic profile across multiple species.
|
Antiviral activity against multidrug resistant HIV1 IIIB containing reverse transcriptase K103N and Y181C mutation infected in human MT2 cells assessed as cytoprotection from infection by MTT colorimetric method
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of benzyloxazoles as non-nucleoside inhibitors of HIV-1 reverse transcriptase to enhance Y181C potency.
Year : 2013
Volume : 23
Issue : 4
First Page : 1110
Last Page : 1113
Authors : Bollini M, Gallardo-Macias R, Spasov KA, Tirado-Rives J, Anderson KS, Jorgensen WL.
Abstract : Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved activity towards Tyr181Cys containing variants was pursued with the assistance of free energy perturbation (FEP) calculations. Optimization of the 4-R substituent in 1 led to ethyl and isopropyl analogs 1e and 1f with 1-7 nM potency towards both the wild-type virus and a Tyr181C variant.
|
Antiviral activity against multidrug resistant HIV1 IIIB containing reverse transcriptase Y181C mutation infected in human MT2 cells assessed as cytoprotection from infection by MTT colorimetric method
|
Human immunodeficiency virus 1
|
0.65
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of benzyloxazoles as non-nucleoside inhibitors of HIV-1 reverse transcriptase to enhance Y181C potency.
Year : 2013
Volume : 23
Issue : 4
First Page : 1110
Last Page : 1113
Authors : Bollini M, Gallardo-Macias R, Spasov KA, Tirado-Rives J, Anderson KS, Jorgensen WL.
Abstract : Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved activity towards Tyr181Cys containing variants was pursued with the assistance of free energy perturbation (FEP) calculations. Optimization of the 4-R substituent in 1 led to ethyl and isopropyl analogs 1e and 1f with 1-7 nM potency towards both the wild-type virus and a Tyr181C variant.
|
Antiviral activity against multidrug resistant HIV1 IIIB containing reverse transcriptase infected in human MT2 cells assessed as cytoprotection from infection by MTT colorimetric method
|
Human immunodeficiency virus 1
|
0.67
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of benzyloxazoles as non-nucleoside inhibitors of HIV-1 reverse transcriptase to enhance Y181C potency.
Year : 2013
Volume : 23
Issue : 4
First Page : 1110
Last Page : 1113
Authors : Bollini M, Gallardo-Macias R, Spasov KA, Tirado-Rives J, Anderson KS, Jorgensen WL.
Abstract : Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved activity towards Tyr181Cys containing variants was pursued with the assistance of free energy perturbation (FEP) calculations. Optimization of the 4-R substituent in 1 led to ethyl and isopropyl analogs 1e and 1f with 1-7 nM potency towards both the wild-type virus and a Tyr181C variant.
|
Antiviral activity against HIV1 RES056 expressing RT K103N/Y181C mutant infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Molecular design, synthesis and biological evaluation of BP-O-DAPY and O-DAPY derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors.
Year : 2013
Volume : 65
First Page : 134
Last Page : 143
Authors : Yang S, Pannecouque C, Daelemans D, Ma XD, Liu Y, Chen FE, De Clercq E.
Abstract : This paper reports the synthesis and antiviral evaluation of a series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine the peculiar structural features of diarylpyrimidine derivatives (DAPYs) and benzophenone derivatives (BPs). The DAPY derivatives bearing benzoyl or alkoxyl substitutes on the A-ring showed the inhibitory activity against wild-type HIV-1 at the cellular level within the range of EC50 values from micromolar to nanomolar. Among these compounds, 1u exhibited the most potent anti-HIV-1 activity (EC50 = 0.06 ± 0.01 μM, SI > 6260), which were about 1.8-fold more active than nevirapine (NVP) and delavirdine (DLV). In addition, the binding modes with HIV-1 RT and the preliminary SAR studies of these derivatives were also considered for further investigation.
|
Antiviral activity against HIV1 3B infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
0.4
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Molecular design, synthesis and biological evaluation of BP-O-DAPY and O-DAPY derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors.
Year : 2013
Volume : 65
First Page : 134
Last Page : 143
Authors : Yang S, Pannecouque C, Daelemans D, Ma XD, Liu Y, Chen FE, De Clercq E.
Abstract : This paper reports the synthesis and antiviral evaluation of a series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine the peculiar structural features of diarylpyrimidine derivatives (DAPYs) and benzophenone derivatives (BPs). The DAPY derivatives bearing benzoyl or alkoxyl substitutes on the A-ring showed the inhibitory activity against wild-type HIV-1 at the cellular level within the range of EC50 values from micromolar to nanomolar. Among these compounds, 1u exhibited the most potent anti-HIV-1 activity (EC50 = 0.06 ± 0.01 μM, SI > 6260), which were about 1.8-fold more active than nevirapine (NVP) and delavirdine (DLV). In addition, the binding modes with HIV-1 RT and the preliminary SAR studies of these derivatives were also considered for further investigation.
|
Inhibition of HIV RT K103N/Y181C mutant by cell based assay
|
Human immunodeficiency virus
|
0.8
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Molecular design, synthesis and biological evaluation of BP-O-DAPY and O-DAPY derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors.
Year : 2013
Volume : 65
First Page : 134
Last Page : 143
Authors : Yang S, Pannecouque C, Daelemans D, Ma XD, Liu Y, Chen FE, De Clercq E.
Abstract : This paper reports the synthesis and antiviral evaluation of a series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine the peculiar structural features of diarylpyrimidine derivatives (DAPYs) and benzophenone derivatives (BPs). The DAPY derivatives bearing benzoyl or alkoxyl substitutes on the A-ring showed the inhibitory activity against wild-type HIV-1 at the cellular level within the range of EC50 values from micromolar to nanomolar. Among these compounds, 1u exhibited the most potent anti-HIV-1 activity (EC50 = 0.06 ± 0.01 μM, SI > 6260), which were about 1.8-fold more active than nevirapine (NVP) and delavirdine (DLV). In addition, the binding modes with HIV-1 RT and the preliminary SAR studies of these derivatives were also considered for further investigation.
|
Antiviral activity against HIV1 3B infected in human MT2 cells assessed as protection against virus-induced cytopathogenicity by MTT assay
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Extension into the entrance channel of HIV-1 reverse transcriptase--crystallography and enhanced solubility.
Year : 2013
Volume : 23
Issue : 18
First Page : 5209
Last Page : 5212
Authors : Bollini M, Frey KM, Cisneros JA, Spasov KA, Das K, Bauman JD, Arnold E, Anderson KS, Jorgensen WL.
Abstract : Non-nucleoside inhibitors of HIV-1 reverse transcriptase (HIV-RT) are reported that feature extension into the entrance channel near Glu138. Complexes of the parent anilinylpyrimidine 1 and the morpholinoethoxy analog 2j with HIV-RT have received crystallographic characterization confirming the designs. Measurement of aqueous solubilities of 2j, 2k, the parent triazene 2a, and other NNRTIs demonstrate profound benefits for addition of the morpholinyl substituent.
|
Antiviral activity against HIV1 3B harboring reverse transcriptase K103N/Y181C double mutant infected in human MT2 cells assessed as protection against virus-induced effect by MTT assay
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of diarylazines as anti-HIV agents with dramatically enhanced solubility.
Year : 2013
Volume : 23
Issue : 18
First Page : 5213
Last Page : 5216
Authors : Bollini M, Cisneros JA, Spasov KA, Anderson KS, Jorgensen WL.
Abstract : Non-nucleoside inhibitors of HIV-1 reverse transcriptase are reported that have ca. 100-fold greater solubility than the structurally related drugs etravirine and rilpivirine, while retaining high anti-viral activity. The solubility enhancements come from strategic placement of a morpholinylalkoxy substituent in the entrance channel of the NNRTI binding site. Compound 4d shows low-nanomolar activity similar to etravirine towards wild-type HIV-1 and key viral variants.
|
Antiviral activity against wild type HIV1 3B infected in human MT2 cells assessed as protection against virus-induced effect by MTT assay
|
Human immunodeficiency virus 1
|
0.67
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of diarylazines as anti-HIV agents with dramatically enhanced solubility.
Year : 2013
Volume : 23
Issue : 18
First Page : 5213
Last Page : 5216
Authors : Bollini M, Cisneros JA, Spasov KA, Anderson KS, Jorgensen WL.
Abstract : Non-nucleoside inhibitors of HIV-1 reverse transcriptase are reported that have ca. 100-fold greater solubility than the structurally related drugs etravirine and rilpivirine, while retaining high anti-viral activity. The solubility enhancements come from strategic placement of a morpholinylalkoxy substituent in the entrance channel of the NNRTI binding site. Compound 4d shows low-nanomolar activity similar to etravirine towards wild-type HIV-1 and key viral variants.
|
Antiviral activity against HIV1 3B harboring reverse transcriptase Y181C mutant infected in human MT2 cells assessed as protection against virus-induced effect by MTT assay
|
Human immunodeficiency virus 1
|
0.65
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of diarylazines as anti-HIV agents with dramatically enhanced solubility.
Year : 2013
Volume : 23
Issue : 18
First Page : 5213
Last Page : 5216
Authors : Bollini M, Cisneros JA, Spasov KA, Anderson KS, Jorgensen WL.
Abstract : Non-nucleoside inhibitors of HIV-1 reverse transcriptase are reported that have ca. 100-fold greater solubility than the structurally related drugs etravirine and rilpivirine, while retaining high anti-viral activity. The solubility enhancements come from strategic placement of a morpholinylalkoxy substituent in the entrance channel of the NNRTI binding site. Compound 4d shows low-nanomolar activity similar to etravirine towards wild-type HIV-1 and key viral variants.
|
Inhibition of HIV wild-type reverse transcriptase by electrochemiluminescence assay
|
Human immunodeficiency virus
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of MK-1439, an orally bioavailable non-nucleoside reverse transcriptase inhibitor potent against a wide range of resistant mutant HIV viruses.
Year : 2014
Volume : 24
Issue : 3
First Page : 917
Last Page : 922
Authors : Côté B, Burch JD, Asante-Appiah E, Bayly C, Bédard L, Blouin M, Campeau LC, Cauchon E, Chan M, Chefson A, Coulombe N, Cromlish W, Debnath S, Deschênes D, Dupont-Gaudet K, Falgueyret JP, Forget R, Gagné S, Gauvreau D, Girardin M, Guiral S, Langlois E, Li CS, Nguyen N, Papp R, Plamondon S, Roy A, Roy S, Seliniotakis R, St-Onge M, Ouellet S, Tawa P, Truchon JF, Vacca J, Wrona M, Yan Y, Ducharme Y.
Abstract : The optimization of a novel series of non-nucleoside reverse transcriptase inhibitors (NNRTI) led to the identification of pyridone 36. In cell cultures, this new NNRTI shows a superior potency profile against a range of wild type and clinically relevant, resistant mutant HIV viruses. The overall favorable preclinical pharmacokinetic profile of 36 led to the prediction of a once daily low dose regimen in human. NNRTI 36, now known as MK-1439, is currently in clinical development for the treatment of HIV infection.
|
Antiviral activity against HIV1 harboring reverse transcriptase K101N/Y181C double mutant infected in human MT4 cells
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of 2-pyridone derivatives as potent HIV-1 NNRTIs using molecular hybridization based on crystallographic overlays.
Year : 2014
Volume : 22
Issue : 6
First Page : 1863
Last Page : 1872
Authors : Chen W, Zhan P, Rai D, De Clercq E, Pannecouque C, Balzarini J, Zhou Z, Liu H, Liu X.
Abstract : Based on crystallographic overlays of the known inhibitors TMC125 and R221239 complexed in RT, we designed a novel series of 4-phenoxy-6-(phenylamino)pyridin-2(1H)-one derivatives as HIV NNRTIs by molecular hybridization approach. The biological testing results indicated that 2-pyridone scaffold of these inhibitors was indispensable for their anti-HIV-1 activity, and substitution of halogen at the 3-position of the 2-pyridone ring would decrease the anti-HIV activity. Four most potent compounds had anti-HIV-1 IIIB activities at low micromolar concentrations (EC₅₀=0.15-0.84 μM), comparable to that of nevirapine and delavidine. Some compounds were selected to test their anti-HIV-1 RT inhibitory action and to perform molecular modeling studies to predict the binding mode of these 2-pyridone derivatives.
|
Antiviral activity against HIV1 harboring reverse transcriptase Y181C mutant infected in human MT4 cells
|
Human immunodeficiency virus 1
|
1.3
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of 2-pyridone derivatives as potent HIV-1 NNRTIs using molecular hybridization based on crystallographic overlays.
Year : 2014
Volume : 22
Issue : 6
First Page : 1863
Last Page : 1872
Authors : Chen W, Zhan P, Rai D, De Clercq E, Pannecouque C, Balzarini J, Zhou Z, Liu H, Liu X.
Abstract : Based on crystallographic overlays of the known inhibitors TMC125 and R221239 complexed in RT, we designed a novel series of 4-phenoxy-6-(phenylamino)pyridin-2(1H)-one derivatives as HIV NNRTIs by molecular hybridization approach. The biological testing results indicated that 2-pyridone scaffold of these inhibitors was indispensable for their anti-HIV-1 activity, and substitution of halogen at the 3-position of the 2-pyridone ring would decrease the anti-HIV activity. Four most potent compounds had anti-HIV-1 IIIB activities at low micromolar concentrations (EC₅₀=0.15-0.84 μM), comparable to that of nevirapine and delavidine. Some compounds were selected to test their anti-HIV-1 RT inhibitory action and to perform molecular modeling studies to predict the binding mode of these 2-pyridone derivatives.
|
Antiviral activity against HIV1 harboring reverse transcriptase K101N mutant infected in human MT4 cells
|
Human immunodeficiency virus 1
|
0.3
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of 2-pyridone derivatives as potent HIV-1 NNRTIs using molecular hybridization based on crystallographic overlays.
Year : 2014
Volume : 22
Issue : 6
First Page : 1863
Last Page : 1872
Authors : Chen W, Zhan P, Rai D, De Clercq E, Pannecouque C, Balzarini J, Zhou Z, Liu H, Liu X.
Abstract : Based on crystallographic overlays of the known inhibitors TMC125 and R221239 complexed in RT, we designed a novel series of 4-phenoxy-6-(phenylamino)pyridin-2(1H)-one derivatives as HIV NNRTIs by molecular hybridization approach. The biological testing results indicated that 2-pyridone scaffold of these inhibitors was indispensable for their anti-HIV-1 activity, and substitution of halogen at the 3-position of the 2-pyridone ring would decrease the anti-HIV activity. Four most potent compounds had anti-HIV-1 IIIB activities at low micromolar concentrations (EC₅₀=0.15-0.84 μM), comparable to that of nevirapine and delavidine. Some compounds were selected to test their anti-HIV-1 RT inhibitory action and to perform molecular modeling studies to predict the binding mode of these 2-pyridone derivatives.
|
Antiviral activity against HIV1 harboring wild type reverse transcriptase infected in human MT4 cells
|
Human immunodeficiency virus 1
|
0.5
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of 2-pyridone derivatives as potent HIV-1 NNRTIs using molecular hybridization based on crystallographic overlays.
Year : 2014
Volume : 22
Issue : 6
First Page : 1863
Last Page : 1872
Authors : Chen W, Zhan P, Rai D, De Clercq E, Pannecouque C, Balzarini J, Zhou Z, Liu H, Liu X.
Abstract : Based on crystallographic overlays of the known inhibitors TMC125 and R221239 complexed in RT, we designed a novel series of 4-phenoxy-6-(phenylamino)pyridin-2(1H)-one derivatives as HIV NNRTIs by molecular hybridization approach. The biological testing results indicated that 2-pyridone scaffold of these inhibitors was indispensable for their anti-HIV-1 activity, and substitution of halogen at the 3-position of the 2-pyridone ring would decrease the anti-HIV activity. Four most potent compounds had anti-HIV-1 IIIB activities at low micromolar concentrations (EC₅₀=0.15-0.84 μM), comparable to that of nevirapine and delavidine. Some compounds were selected to test their anti-HIV-1 RT inhibitory action and to perform molecular modeling studies to predict the binding mode of these 2-pyridone derivatives.
|
Antiviral activity against wild type HIV1 3B infected in human MT2 cells assessed as protection from virus-induced cytopathicity by MTT assay
|
Human immunodeficiency virus 1
|
0.67
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Picomolar Inhibitors of HIV-1 Reverse Transcriptase: Design and Crystallography of Naphthyl Phenyl Ethers.
Year : 2014
Volume : 5
Issue : 11
First Page : 1259
Last Page : 1262
Authors : Lee WG, Frey KM, Gallardo-Macias R, Spasov KA, Bollini M, Anderson KS, Jorgensen WL.
Abstract : Catechol diethers that incorporate a 6-cyano-1-naphthyl substituent have been explored as non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). Promising compounds are reported that show midpicomolar activity against the wild-type virus and sub-20 nM activity against viral variants bearing Tyr181Cys and Lys103Asn mutations in HIV-RT. An X-ray crystal structure at 2.49 Å resolution is also reported for the key compound 6e with HIV-RT.
|
Antiviral activity against wild type HIV1 harboring reverse transcriptase Y181C mutant infected in human MT2 cells assessed as protection from virus-induced cytopathicity by MTT assay
|
Human immunodeficiency virus 1
|
0.65
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Picomolar Inhibitors of HIV-1 Reverse Transcriptase: Design and Crystallography of Naphthyl Phenyl Ethers.
Year : 2014
Volume : 5
Issue : 11
First Page : 1259
Last Page : 1262
Authors : Lee WG, Frey KM, Gallardo-Macias R, Spasov KA, Bollini M, Anderson KS, Jorgensen WL.
Abstract : Catechol diethers that incorporate a 6-cyano-1-naphthyl substituent have been explored as non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). Promising compounds are reported that show midpicomolar activity against the wild-type virus and sub-20 nM activity against viral variants bearing Tyr181Cys and Lys103Asn mutations in HIV-RT. An X-ray crystal structure at 2.49 Å resolution is also reported for the key compound 6e with HIV-RT.
|
Antiviral activity against wild type HIV1 harboring reverse transcriptase K103N/Y181C mutant infected in human MT2 cells assessed as protection from virus-induced cytopathicity by MTT assay
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Picomolar Inhibitors of HIV-1 Reverse Transcriptase: Design and Crystallography of Naphthyl Phenyl Ethers.
Year : 2014
Volume : 5
Issue : 11
First Page : 1259
Last Page : 1262
Authors : Lee WG, Frey KM, Gallardo-Macias R, Spasov KA, Bollini M, Anderson KS, Jorgensen WL.
Abstract : Catechol diethers that incorporate a 6-cyano-1-naphthyl substituent have been explored as non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). Promising compounds are reported that show midpicomolar activity against the wild-type virus and sub-20 nM activity against viral variants bearing Tyr181Cys and Lys103Asn mutations in HIV-RT. An X-ray crystal structure at 2.49 Å resolution is also reported for the key compound 6e with HIV-RT.
|
Antiviral activity against wild type HIV1 3B infected in human MT2 cells assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
0.49
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Physicochemical property-driven optimization of diarylaniline compounds as potent HIV-1 non-nucleoside reverse transcriptase inhibitors.
Year : 2014
Volume : 24
Issue : 16
First Page : 3719
Last Page : 3723
Authors : Liu N, Qin B, Sun LQ, Yu F, Lu L, Jiang S, Lee KH, Xie L.
Abstract : Using physicochemical property-driven optimization, twelve new diarylaniline compounds (DAANs) (7a-h, 11a-b and 12a-b) were designed and synthesized. Among them, compounds 12a-b not only showed high potency (EC50 0.96-4.92 nM) against both wild-type and drug-resistant viral strains with the lowest fold change (FC 0.91 and 5.13), but also displayed acceptable drug-like properties based on aqueous solubility and lipophilicity (LE>0.3, LLE>5, LELP<10). The correlations between potency and physicochemical properties of these DAAN analogues are also described. Compounds 12a-b merit further development as potent clinical trial candidates against AIDS.
|
Antiviral activity against wild type HIV1 A17 expressing K103N/Y181C mutant infected in human MT2 cells assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
9.03
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Physicochemical property-driven optimization of diarylaniline compounds as potent HIV-1 non-nucleoside reverse transcriptase inhibitors.
Year : 2014
Volume : 24
Issue : 16
First Page : 3719
Last Page : 3723
Authors : Liu N, Qin B, Sun LQ, Yu F, Lu L, Jiang S, Lee KH, Xie L.
Abstract : Using physicochemical property-driven optimization, twelve new diarylaniline compounds (DAANs) (7a-h, 11a-b and 12a-b) were designed and synthesized. Among them, compounds 12a-b not only showed high potency (EC50 0.96-4.92 nM) against both wild-type and drug-resistant viral strains with the lowest fold change (FC 0.91 and 5.13), but also displayed acceptable drug-like properties based on aqueous solubility and lipophilicity (LE>0.3, LLE>5, LELP<10). The correlations between potency and physicochemical properties of these DAAN analogues are also described. Compounds 12a-b merit further development as potent clinical trial candidates against AIDS.
|
Antiviral activity against HIV-1 X4 expressing wild-type reverse transcriptase infected in human CD4+ T cells for 3 days by FACS analysis
|
Human immunodeficiency virus 1
|
13.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Potent Inhibitors Active against HIV Reverse Transcriptase with K101P, a Mutation Conferring Rilpivirine Resistance.
Year : 2015
Volume : 6
Issue : 10
First Page : 1075
Last Page : 1079
Authors : Gray WT, Frey KM, Laskey SB, Mislak AC, Spasov KA, Lee WG, Bollini M, Siliciano RF, Jorgensen WL, Anderson KS.
Abstract : Catechol diether compounds have nanomolar antiviral and enzymatic activity against HIV with reverse transcriptase (RT) variants containing K101P, a mutation that confers high-level resistance to FDA-approved non-nucleoside inhibitors efavirenz and rilpivirine. Kinetic data suggests that RT (K101P) variants are as catalytically fit as wild-type and thus can potentially increase in the viral population as more antiviral regimens include efavirenz or rilpivirine. Comparison of wild-type structures and a new crystal structure of RT (K101P) in complex with a leading compound confirms that the K101P mutation is not a liability for the catechol diethers while suggesting that key interactions are lost with efavirenz and rilpivirine.
|
Antiviral activity against HIV-1 X4 expressing reverse transcriptase K103N mutant infected in human CD4+ T cells for 3 days by FACS analysis
|
Human immunodeficiency virus 1
|
13.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Potent Inhibitors Active against HIV Reverse Transcriptase with K101P, a Mutation Conferring Rilpivirine Resistance.
Year : 2015
Volume : 6
Issue : 10
First Page : 1075
Last Page : 1079
Authors : Gray WT, Frey KM, Laskey SB, Mislak AC, Spasov KA, Lee WG, Bollini M, Siliciano RF, Jorgensen WL, Anderson KS.
Abstract : Catechol diether compounds have nanomolar antiviral and enzymatic activity against HIV with reverse transcriptase (RT) variants containing K101P, a mutation that confers high-level resistance to FDA-approved non-nucleoside inhibitors efavirenz and rilpivirine. Kinetic data suggests that RT (K101P) variants are as catalytically fit as wild-type and thus can potentially increase in the viral population as more antiviral regimens include efavirenz or rilpivirine. Comparison of wild-type structures and a new crystal structure of RT (K101P) in complex with a leading compound confirms that the K101P mutation is not a liability for the catechol diethers while suggesting that key interactions are lost with efavirenz and rilpivirine.
|
Antiviral activity against HIV-1 X4 expressing reverse transcriptase Y181C mutant infected in human CD4+ T cells for 3 days by FACS analysis
|
Human immunodeficiency virus 1
|
51.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Potent Inhibitors Active against HIV Reverse Transcriptase with K101P, a Mutation Conferring Rilpivirine Resistance.
Year : 2015
Volume : 6
Issue : 10
First Page : 1075
Last Page : 1079
Authors : Gray WT, Frey KM, Laskey SB, Mislak AC, Spasov KA, Lee WG, Bollini M, Siliciano RF, Jorgensen WL, Anderson KS.
Abstract : Catechol diether compounds have nanomolar antiviral and enzymatic activity against HIV with reverse transcriptase (RT) variants containing K101P, a mutation that confers high-level resistance to FDA-approved non-nucleoside inhibitors efavirenz and rilpivirine. Kinetic data suggests that RT (K101P) variants are as catalytically fit as wild-type and thus can potentially increase in the viral population as more antiviral regimens include efavirenz or rilpivirine. Comparison of wild-type structures and a new crystal structure of RT (K101P) in complex with a leading compound confirms that the K101P mutation is not a liability for the catechol diethers while suggesting that key interactions are lost with efavirenz and rilpivirine.
|
Inhibition of wild-type HIV-1 reverse transcriptase by fluorescence assay
|
Human immunodeficiency virus 1
|
15.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Potent Inhibitors Active against HIV Reverse Transcriptase with K101P, a Mutation Conferring Rilpivirine Resistance.
Year : 2015
Volume : 6
Issue : 10
First Page : 1075
Last Page : 1079
Authors : Gray WT, Frey KM, Laskey SB, Mislak AC, Spasov KA, Lee WG, Bollini M, Siliciano RF, Jorgensen WL, Anderson KS.
Abstract : Catechol diether compounds have nanomolar antiviral and enzymatic activity against HIV with reverse transcriptase (RT) variants containing K101P, a mutation that confers high-level resistance to FDA-approved non-nucleoside inhibitors efavirenz and rilpivirine. Kinetic data suggests that RT (K101P) variants are as catalytically fit as wild-type and thus can potentially increase in the viral population as more antiviral regimens include efavirenz or rilpivirine. Comparison of wild-type structures and a new crystal structure of RT (K101P) in complex with a leading compound confirms that the K101P mutation is not a liability for the catechol diethers while suggesting that key interactions are lost with efavirenz and rilpivirine.
|
Antiviral activity against R5-tropic HIV1 subtype B BaL infected in human TZM-bl cells assessed as viral inhibition pre-incubated for 30 mins prior to infection measured after 48 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
0.72
nM
|
|
Journal : J. Med. Chem.
Title : 2,6-Di(arylamino)-3-fluoropyridine Derivatives as HIV Non-Nucleoside Reverse Transcriptase Inhibitors.
Year : 2016
Volume : 59
Issue : 5
First Page : 1854
Last Page : 1868
Authors : Sergeyev S, Yadav AK, Franck P, Michiels J, Lewi P, Heeres J, Vanham G, Ariën KK, Vande Velde CM, De Winter H, Maes BU.
Abstract : New non-nucleoside reverse transcriptase inhibitors (NNRTI), which are similar in structure to earlier described di(arylamino)pyrimidines but featuring a 2,6-di(arylamino)-3-fluoropyridine, 2,4-di(arylamino)-5-fluoropyrimidine, or 1,3-di(arylamino)-4-fluorobenzene moiety instead of a 2,4-disubstituted pyrimidine moiety, are reported. The short and practical synthesis of novel NNRTI relies on two sequential Pd-catalyzed aminations as the key steps. It is demonstrated through direct comparison with reference compounds that the presence of a fluorine atom increases the in vitro anti-HIV activity, both against the wild type virus and drug-resistant mutant strains.
|
Antiviral activity against nevirapine resistant R5-tropic HIV1 subtype C VI829 expressing reverse transcriptase Y181C mutant infected in human TZM-bl cells assessed as viral inhibition pre-incubated for 30 mins prior to infection measured after 48 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
2.5
nM
|
|
Journal : J. Med. Chem.
Title : 2,6-Di(arylamino)-3-fluoropyridine Derivatives as HIV Non-Nucleoside Reverse Transcriptase Inhibitors.
Year : 2016
Volume : 59
Issue : 5
First Page : 1854
Last Page : 1868
Authors : Sergeyev S, Yadav AK, Franck P, Michiels J, Lewi P, Heeres J, Vanham G, Ariën KK, Vande Velde CM, De Winter H, Maes BU.
Abstract : New non-nucleoside reverse transcriptase inhibitors (NNRTI), which are similar in structure to earlier described di(arylamino)pyrimidines but featuring a 2,6-di(arylamino)-3-fluoropyridine, 2,4-di(arylamino)-5-fluoropyrimidine, or 1,3-di(arylamino)-4-fluorobenzene moiety instead of a 2,4-disubstituted pyrimidine moiety, are reported. The short and practical synthesis of novel NNRTI relies on two sequential Pd-catalyzed aminations as the key steps. It is demonstrated through direct comparison with reference compounds that the presence of a fluorine atom increases the in vitro anti-HIV activity, both against the wild type virus and drug-resistant mutant strains.
|
Antiviral activity against efavirenz resistant R5-tropic HIV1 subtype C VI829 expressing reverse transcriptase L100I-K103N mutant infected in human TZM-bl cells assessed as viral inhibition pre-incubated for 30 mins prior to infection measured after 48 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
3.6
nM
|
|
Journal : J. Med. Chem.
Title : 2,6-Di(arylamino)-3-fluoropyridine Derivatives as HIV Non-Nucleoside Reverse Transcriptase Inhibitors.
Year : 2016
Volume : 59
Issue : 5
First Page : 1854
Last Page : 1868
Authors : Sergeyev S, Yadav AK, Franck P, Michiels J, Lewi P, Heeres J, Vanham G, Ariën KK, Vande Velde CM, De Winter H, Maes BU.
Abstract : New non-nucleoside reverse transcriptase inhibitors (NNRTI), which are similar in structure to earlier described di(arylamino)pyrimidines but featuring a 2,6-di(arylamino)-3-fluoropyridine, 2,4-di(arylamino)-5-fluoropyrimidine, or 1,3-di(arylamino)-4-fluorobenzene moiety instead of a 2,4-disubstituted pyrimidine moiety, are reported. The short and practical synthesis of novel NNRTI relies on two sequential Pd-catalyzed aminations as the key steps. It is demonstrated through direct comparison with reference compounds that the presence of a fluorine atom increases the in vitro anti-HIV activity, both against the wild type virus and drug-resistant mutant strains.
|
Antiviral activity against HIV1 NL4.3 expressing reverse transcriptase K103N mutant infected in human TZM-bl cells assessed as viral inhibition pre-incubated for 30 mins prior to infection measured after 48 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
0.7
nM
|
|
Journal : J. Med. Chem.
Title : 2,6-Di(arylamino)-3-fluoropyridine Derivatives as HIV Non-Nucleoside Reverse Transcriptase Inhibitors.
Year : 2016
Volume : 59
Issue : 5
First Page : 1854
Last Page : 1868
Authors : Sergeyev S, Yadav AK, Franck P, Michiels J, Lewi P, Heeres J, Vanham G, Ariën KK, Vande Velde CM, De Winter H, Maes BU.
Abstract : New non-nucleoside reverse transcriptase inhibitors (NNRTI), which are similar in structure to earlier described di(arylamino)pyrimidines but featuring a 2,6-di(arylamino)-3-fluoropyridine, 2,4-di(arylamino)-5-fluoropyrimidine, or 1,3-di(arylamino)-4-fluorobenzene moiety instead of a 2,4-disubstituted pyrimidine moiety, are reported. The short and practical synthesis of novel NNRTI relies on two sequential Pd-catalyzed aminations as the key steps. It is demonstrated through direct comparison with reference compounds that the presence of a fluorine atom increases the in vitro anti-HIV activity, both against the wild type virus and drug-resistant mutant strains.
|
Antiviral activity against HIV1 NL4.3 expressing reverse transcriptase K103N-Y181C mutant infected in human TZM-bl cells assessed as viral inhibition pre-incubated for 30 mins prior to infection measured after 48 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
3.1
nM
|
|
Journal : J. Med. Chem.
Title : 2,6-Di(arylamino)-3-fluoropyridine Derivatives as HIV Non-Nucleoside Reverse Transcriptase Inhibitors.
Year : 2016
Volume : 59
Issue : 5
First Page : 1854
Last Page : 1868
Authors : Sergeyev S, Yadav AK, Franck P, Michiels J, Lewi P, Heeres J, Vanham G, Ariën KK, Vande Velde CM, De Winter H, Maes BU.
Abstract : New non-nucleoside reverse transcriptase inhibitors (NNRTI), which are similar in structure to earlier described di(arylamino)pyrimidines but featuring a 2,6-di(arylamino)-3-fluoropyridine, 2,4-di(arylamino)-5-fluoropyrimidine, or 1,3-di(arylamino)-4-fluorobenzene moiety instead of a 2,4-disubstituted pyrimidine moiety, are reported. The short and practical synthesis of novel NNRTI relies on two sequential Pd-catalyzed aminations as the key steps. It is demonstrated through direct comparison with reference compounds that the presence of a fluorine atom increases the in vitro anti-HIV activity, both against the wild type virus and drug-resistant mutant strains.
|
Antiviral activity against rilpivirine resistant HIV1 harboring reverse transcriptase E138K mutant assessed as inhibition of viral infection in human TZM-bl cells measured after 1 day by luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
5.2
nM
|
|
Journal : J. Med. Chem.
Title : Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitor Agents: Optimization of Diarylanilines with High Potency against Wild-Type and Rilpivirine-Resistant E138K Mutant Virus.
Year : 2016
Volume : 59
Issue : 8
First Page : 3689
Last Page : 3704
Authors : Liu N, Wei L, Huang L, Yu F, Zheng W, Qin B, Zhu DQ, Morris-Natschke SL, Jiang S, Chen CH, Lee KH, Xie L.
Abstract : Three series (6, 13, and 14) of new diarylaniline (DAAN) analogues were designed, synthesized, and evaluated for anti-HIV potency, especially against the E138K viral strain with a major mutation conferring resistance to the new-generation non-nucleoside reverse transcriptase inhibitor drug rilpivirine (1b). Promising new compounds were then assessed for physicochemical and associated pharmaceutical properties, including aqueous solubility, log P value, and metabolic stability, as well as predicted lipophilic parameters of ligand efficiency, ligand lipophilic efficiency, and ligand efficiency-dependent lipophilicity indices, which are associated with ADME property profiles. Compounds 6a, 14c, and 14d showed high potency against the 1b-resistant E138K mutated viral strain as well as good balance between anti-HIV-1 activity and desirable druglike properties. From the perspective of optimizing future NNRTI compounds as clinical trial candidates, computational modeling results provided valuable information about how the R(1) group might provide greater efficacy against the E138K mutant.
|
Antiviral activity against HIV1 NL4-3 assessed as inhibition of viral infection in human TZM-bl cells measured after 1 day by luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
0.52
nM
|
|
Journal : J. Med. Chem.
Title : Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitor Agents: Optimization of Diarylanilines with High Potency against Wild-Type and Rilpivirine-Resistant E138K Mutant Virus.
Year : 2016
Volume : 59
Issue : 8
First Page : 3689
Last Page : 3704
Authors : Liu N, Wei L, Huang L, Yu F, Zheng W, Qin B, Zhu DQ, Morris-Natschke SL, Jiang S, Chen CH, Lee KH, Xie L.
Abstract : Three series (6, 13, and 14) of new diarylaniline (DAAN) analogues were designed, synthesized, and evaluated for anti-HIV potency, especially against the E138K viral strain with a major mutation conferring resistance to the new-generation non-nucleoside reverse transcriptase inhibitor drug rilpivirine (1b). Promising new compounds were then assessed for physicochemical and associated pharmaceutical properties, including aqueous solubility, log P value, and metabolic stability, as well as predicted lipophilic parameters of ligand efficiency, ligand lipophilic efficiency, and ligand efficiency-dependent lipophilicity indices, which are associated with ADME property profiles. Compounds 6a, 14c, and 14d showed high potency against the 1b-resistant E138K mutated viral strain as well as good balance between anti-HIV-1 activity and desirable druglike properties. From the perspective of optimizing future NNRTI compounds as clinical trial candidates, computational modeling results provided valuable information about how the R(1) group might provide greater efficacy against the E138K mutant.
|
Antiviral activity against HIV1 3B infected in human MT2 cells measured on day 4 post infection by p24 ELISA method
|
Human immunodeficiency virus 1
|
0.49
nM
|
|
Journal : J. Med. Chem.
Title : Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitor Agents: Optimization of Diarylanilines with High Potency against Wild-Type and Rilpivirine-Resistant E138K Mutant Virus.
Year : 2016
Volume : 59
Issue : 8
First Page : 3689
Last Page : 3704
Authors : Liu N, Wei L, Huang L, Yu F, Zheng W, Qin B, Zhu DQ, Morris-Natschke SL, Jiang S, Chen CH, Lee KH, Xie L.
Abstract : Three series (6, 13, and 14) of new diarylaniline (DAAN) analogues were designed, synthesized, and evaluated for anti-HIV potency, especially against the E138K viral strain with a major mutation conferring resistance to the new-generation non-nucleoside reverse transcriptase inhibitor drug rilpivirine (1b). Promising new compounds were then assessed for physicochemical and associated pharmaceutical properties, including aqueous solubility, log P value, and metabolic stability, as well as predicted lipophilic parameters of ligand efficiency, ligand lipophilic efficiency, and ligand efficiency-dependent lipophilicity indices, which are associated with ADME property profiles. Compounds 6a, 14c, and 14d showed high potency against the 1b-resistant E138K mutated viral strain as well as good balance between anti-HIV-1 activity and desirable druglike properties. From the perspective of optimizing future NNRTI compounds as clinical trial candidates, computational modeling results provided valuable information about how the R(1) group might provide greater efficacy against the E138K mutant.
|
Antiviral activity against multi-NRTI resistant HIV1 A17 harboring reverse transcriptase K103N/Y181C double mutant infected in human MT2 cells measured on day 4 post infection by p24 ELISA method
|
Human immunodeficiency virus 1
|
9.03
nM
|
|
Journal : J. Med. Chem.
Title : Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitor Agents: Optimization of Diarylanilines with High Potency against Wild-Type and Rilpivirine-Resistant E138K Mutant Virus.
Year : 2016
Volume : 59
Issue : 8
First Page : 3689
Last Page : 3704
Authors : Liu N, Wei L, Huang L, Yu F, Zheng W, Qin B, Zhu DQ, Morris-Natschke SL, Jiang S, Chen CH, Lee KH, Xie L.
Abstract : Three series (6, 13, and 14) of new diarylaniline (DAAN) analogues were designed, synthesized, and evaluated for anti-HIV potency, especially against the E138K viral strain with a major mutation conferring resistance to the new-generation non-nucleoside reverse transcriptase inhibitor drug rilpivirine (1b). Promising new compounds were then assessed for physicochemical and associated pharmaceutical properties, including aqueous solubility, log P value, and metabolic stability, as well as predicted lipophilic parameters of ligand efficiency, ligand lipophilic efficiency, and ligand efficiency-dependent lipophilicity indices, which are associated with ADME property profiles. Compounds 6a, 14c, and 14d showed high potency against the 1b-resistant E138K mutated viral strain as well as good balance between anti-HIV-1 activity and desirable druglike properties. From the perspective of optimizing future NNRTI compounds as clinical trial candidates, computational modeling results provided valuable information about how the R(1) group might provide greater efficacy against the E138K mutant.
|
Inhibition of wild type HIV1 NL4-3 reverse transcriptase infected in human TZM-b1 cells after 2 days by bright Glo-luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
0.44
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Drug-like property-driven optimization of 4-substituted 1,5-diarylanilines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors against rilpivirine-resistant mutant virus.
Year : 2017
Volume : 27
Issue : 12
First Page : 2788
Last Page : 2792
Authors : Wei L, Wang HL, Huang L, Chen CH, Morris-Natschke SL, Lee KH, Xie L.
Abstract : On the basis of our prior structure-activity relationship (SAR) results, our current lead optimization of 1,5-diarylanilines (DAANs) focused on the 4-substituent (R1) on the central phenyl ring as a modifiable position related simultaneously to improved drug resistance profiles and drug-like properties. Newly synthesized p-cyanovinyl-DAANs (8a-8g) with different R1 side chains plus prior active p-cyanoethyl-DAANs (4a-4c) were evaluated not only for anti-HIV potency against both wild-type HIV virus and rilpivirine-resistant (E138K, E138K+M184I) viral replication, but also for multiple drug-like properties, including aqueous solubility, lipophilicity, and metabolic stability in human liver microsomes and human plasma. This study revealed that both ester and amide R1 substituents led to low nanomolar anti-HIV potency against wild-type and rilpivirine-resistant viral strains (E138K-resistance fold changes<3). The N-substituted amide-R1 side chains were superior to ester-R1 likely due to improved aqueous solubility, lipophilicity, and higher metabolic stability in vitro. Thus, three amide-DAANs 8e, 4a, and 4b were identified with high potency against wild-type and rilpivirine-resistant viral strains and multiple desirable drug-like properties.
|
Inhibition of rilpivirine-resistant HIV1 NL4-3 reverse transcriptase E138K mutant infected in human TZM-b1 cells after 2 days by bright Glo-luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
3.55
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Drug-like property-driven optimization of 4-substituted 1,5-diarylanilines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors against rilpivirine-resistant mutant virus.
Year : 2017
Volume : 27
Issue : 12
First Page : 2788
Last Page : 2792
Authors : Wei L, Wang HL, Huang L, Chen CH, Morris-Natschke SL, Lee KH, Xie L.
Abstract : On the basis of our prior structure-activity relationship (SAR) results, our current lead optimization of 1,5-diarylanilines (DAANs) focused on the 4-substituent (R1) on the central phenyl ring as a modifiable position related simultaneously to improved drug resistance profiles and drug-like properties. Newly synthesized p-cyanovinyl-DAANs (8a-8g) with different R1 side chains plus prior active p-cyanoethyl-DAANs (4a-4c) were evaluated not only for anti-HIV potency against both wild-type HIV virus and rilpivirine-resistant (E138K, E138K+M184I) viral replication, but also for multiple drug-like properties, including aqueous solubility, lipophilicity, and metabolic stability in human liver microsomes and human plasma. This study revealed that both ester and amide R1 substituents led to low nanomolar anti-HIV potency against wild-type and rilpivirine-resistant viral strains (E138K-resistance fold changes<3). The N-substituted amide-R1 side chains were superior to ester-R1 likely due to improved aqueous solubility, lipophilicity, and higher metabolic stability in vitro. Thus, three amide-DAANs 8e, 4a, and 4b were identified with high potency against wild-type and rilpivirine-resistant viral strains and multiple desirable drug-like properties.
|
Inhibition of rilpivirine-resistant HIV1 NL4-3 reverse transcriptase E138K/M1841 double mutant infected in human TZM-b1 cells after 2 days by bright Glo-luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
2.38
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Drug-like property-driven optimization of 4-substituted 1,5-diarylanilines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors against rilpivirine-resistant mutant virus.
Year : 2017
Volume : 27
Issue : 12
First Page : 2788
Last Page : 2792
Authors : Wei L, Wang HL, Huang L, Chen CH, Morris-Natschke SL, Lee KH, Xie L.
Abstract : On the basis of our prior structure-activity relationship (SAR) results, our current lead optimization of 1,5-diarylanilines (DAANs) focused on the 4-substituent (R1) on the central phenyl ring as a modifiable position related simultaneously to improved drug resistance profiles and drug-like properties. Newly synthesized p-cyanovinyl-DAANs (8a-8g) with different R1 side chains plus prior active p-cyanoethyl-DAANs (4a-4c) were evaluated not only for anti-HIV potency against both wild-type HIV virus and rilpivirine-resistant (E138K, E138K+M184I) viral replication, but also for multiple drug-like properties, including aqueous solubility, lipophilicity, and metabolic stability in human liver microsomes and human plasma. This study revealed that both ester and amide R1 substituents led to low nanomolar anti-HIV potency against wild-type and rilpivirine-resistant viral strains (E138K-resistance fold changes<3). The N-substituted amide-R1 side chains were superior to ester-R1 likely due to improved aqueous solubility, lipophilicity, and higher metabolic stability in vitro. Thus, three amide-DAANs 8e, 4a, and 4b were identified with high potency against wild-type and rilpivirine-resistant viral strains and multiple desirable drug-like properties.
|
Antiviral activity against wild-type HIV-1 NL4-3 infected in human TZM-bl cells assessed as inhibition of viral replication after 2 days by bright Glo-luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
0.9
nM
|
|
Journal : Eur J Med Chem
Title : Targeting the entrance channel of NNIBP: Discovery of diarylnicotinamide 1,4-disubstituted 1,2,3-triazoles as novel HIV-1 NNRTIs with high potency against wild-type and E138K mutant virus.
Year : 2018
Volume : 151
First Page : 339
Last Page : 350
Authors : Tian Y, Liu Z, Liu J, Huang B, Kang D, Zhang H, De Clercq E, Daelemans D, Pannecouque C, Lee KH, Chen CH, Zhan P, Liu X.
Abstract : Inspired by our previous efforts on the modifications of diarylpyrimidines as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) and reported crystallography study, novel diarylnicotinamide derivatives were designed with a "triazole tail" occupying the entrance channel in the NNRTI binding pocket of the reverse transcriptase to afford additional interactions. The newly designed compounds were then synthesized and evaluated for their anti-HIV activities in MT-4 cells. All the compounds showed excellent to good activity against wild-type HIV-1 strain with EC50 of 0.02-1.77 μM. Evaluations of selected compounds against more drug-resistant strains showed these compounds had advantage of inhibiting E138K mutant virus which is a key drug-resistant mutant to the new generation of NNRTIs. Among this series, propionitrile (3b2, EC50(IIIB) = 0.020 μM, EC50(E138K) = 0.015 μM, CC50 = 40.15 μM), pyrrolidin-1-ylmethanone (3b8, EC50(IIIB) = 0.020 μM, EC50(E138K) = 0.014 μM, CC50 = 58.09 μM) and morpholinomethanone (3b9, EC50(IIIB) = 0.020 μM, EC50(E138K) = 0.027 μM, CC50 = 180.90 μM) derivatives are the three most promising compounds which are equally potent to the marketed drug Etravirine against E138K mutant strain but with much lower cytotoxicity. Furthermore, detailed SAR, inhibitory activity against RT and docking study of the representative compounds are also discussed.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
82.1
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of HIV1 Reverse transcriptase polymerase assessed as decrease in digoxigenin and biotin-dUTP incorporation into DNA using poly(A)/oligo(dT)15 as template/primer by ELISA
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : Bioorg Med Chem
Title : Biological evaluation of molecules of the azaBINOL class as antiviral agents: Inhibition of HIV-1 RNase H activity by 7-isopropoxy-8-(naphth-1-yl)quinoline.
Year : 2019
Volume : 27
Issue : 16
First Page : 3595
Last Page : 3604
Authors : Overacker RD, Banerjee S, Neuhaus GF, Milicevic Sephton S, Herrmann A, Strother JA, Brack-Werner R, Blakemore PR, Loesgen S.
Abstract : Inspired by bioactive biaryl-containing natural products found in plants and the marine environment, a series of synthetic compounds belonging to the azaBINOL chiral ligand family was evaluated for antiviral activity against HIV-1. Testing of 39 unique azaBINOLs and two BINOLs in a single-round infectivity assay resulted in the identification of three promising antiviral compounds, including 7-isopropoxy-8-(naphth-1-yl)quinoline (azaBINOL B#24), which exhibited low-micromolar activity without associated cytotoxicity. The active compounds and several close structural analogues were further tested against three different HIV-1 envelope pseudotyped viruses as well as in a full-virus replication system (EASY-HIT). The in vitro studies indicated that azaBINOL B#24 acts on early stages of viral replication before viral assembly and budding. Next we explored B#24's activity against HIV-1 reverse transcriptase (RT) and individually tested for polymerase and RNase H activity. The azaBINOL B#24 inhibits RNase H activity and binds directly to the HIV-1 RT enzyme. Additionally, we observe additive inhibitory activity against pseudotyped viruses when B#24 is dosed in competition with the clinically used non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz. When tested against a multi-drug resistant HIV-1 isolate with drug resistance associated mutations in regions encoding for HIV-1 RT and protease, B#24 only exhibits a 5.1-fold net decrease in IC<sub>50</sub> value, while efavirenz' activity decreases by 7.6-fold. These results indicate that azaBINOL B#24 is a potentially viable, novel lead for the development of new HIV-1 RNase H inhibitors. Furthermore, this study demonstrates that the survey of libraries of synthetic compounds, designed purely with the goal of facilitating chemical synthesis in mind, may yield unexpected and selective drug leads for the development of new antiviral agents.
|
Antiviral activity against HIV1 RES056 infected in human MT4 cells assessed as protection against virus-induced cytopathic effect incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
10.7
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Antiviral activity against HIV1 3B infected in human MT4 cells assessed as protection against virus-induced cytopathic effect incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Antiviral activity against HIV1 expressing RT L100I mutant infected in human MT4 cells assessed as protection against virus-induced cytopathic effect incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
1.54
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Antiviral activity against HIV1 expressing RT K103N mutant infected in human MT4 cells assessed as protection against virus-induced cytopathic effect incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
1.31
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Antiviral activity against HIV1 expressing RT Y181C mutant infected in human MT4 cells assessed as protection against virus-induced cytopathic effect incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
4.73
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Antiviral activity against HIV1 expressing RT Y188L mutant infected in human MT4 cells assessed as protection against virus-induced cytopathic effect incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
79.4
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Antiviral activity against HIV1 expressing RT E138K mutant infected in human MT4 cells assessed as protection against virus-induced cytopathic effect incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
5.75
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Antiviral activity against HIV1 expressing RT F227L + V106A mutant infected in human MT4 cells assessed as protection against virus-induced cytopathic effect incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
81.6
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Antiviral activity against HIV1 3B infected in human MT4 cells grown under 30 passages in absence of test compound assessed as protection against virus-induced cytopathic effect incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
0.9
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Antiviral activity against HIV1 3B infected in human MT4 cells grown under 30 passages in presence of 4-[[4-[[4-(4-cyano-2,6-dimethylphenoxy)thieno[3,2-d]pyrimidin-2-yl]amino]-1-piperidyl]methyl]benzenesulfonamide assessed as protection against virus-induced cytopathic effect incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
90.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Antiviral activity against HIV1 3B infected in human MT4 cells grown under 30 passages in presence of 4-[[4-[[4-[4-[2-cyanovinyl]-2,6-dimethylphenoxy]thieno[3,2-d]pyrimidin-2-yl]amino]-1-piperidyl]methyl]benzenesulfonamide assessed as protection against virus-induced cytopathic effect incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
60.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Inhibition of HIV1 RT in presence of reconstituted template and viral nucleotides [digoxigenin (DIG)-dUTP, biotin-dUTP and dTTP] incubated for 1 hr by ELISA method
|
Human immunodeficiency virus 1
|
15.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Inhibition of HIV1 RT L100I mutant in presence of reconstituted template and viral nucleotides [digoxigenin (DIG)-dUTP, biotin-dUTP and dTTP] incubated for 1 hr by ELISA method
|
Human immunodeficiency virus 1
|
24.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Inhibition of HIV1 RT K103N mutant in presence of reconstituted template and viral nucleotides [digoxigenin (DIG)-dUTP, biotin-dUTP and dTTP] incubated for 1 hr by ELISA method
|
Human immunodeficiency virus 1
|
27.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Inhibition of HIV1 RT Y181C mutant in presence of reconstituted template and viral nucleotides [digoxigenin (DIG)-dUTP, biotin-dUTP and dTTP] incubated for 1 hr by ELISA method
|
Human immunodeficiency virus 1
|
21.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Inhibition of HIV1 RT Y188L mutant in presence of reconstituted template and viral nucleotides [digoxigenin (DIG)-dUTP, biotin-dUTP and dTTP] incubated for 1 hr by ELISA method
|
Human immunodeficiency virus 1
|
84.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Inhibition of HIV1 RT E138K mutant in presence of reconstituted template and viral nucleotides [digoxigenin (DIG)-dUTP, biotin-dUTP and dTTP] incubated for 1 hr by ELISA method
|
Human immunodeficiency virus 1
|
41.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Inhibition of HIV1 RT V106A/F227L mutant in presence of reconstituted template and viral nucleotides [digoxigenin (DIG)-dUTP, biotin-dUTP and dTTP] incubated for 1 hr by ELISA method
|
Human immunodeficiency virus 1
|
15.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Inhibition of HIV1 RT K103N/Y181C mutant in presence of reconstituted template and viral nucleotides [digoxigenin (DIG)-dUTP, biotin-dUTP and dTTP] incubated for 1 hr by ELISA method
|
Human immunodeficiency virus 1
|
23.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Inhibition of CYP2C9 in human liver microsomes using diclofenac substrate incubated for 10 mins in presence of NADPH
|
Homo sapiens
|
346.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Inhibition of CYP2C19 in human liver microsomes using S-mephenytoin substrate incubated for 10 mins in presence of NADPH
|
Homo sapiens
|
335.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Inhibition of human ERG expressed in HEK293 cells by whole cell electrophysiology assay
|
Homo sapiens
|
500.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Antiviral activity against HIV1 3B infected in human MT4 cells assessed as inhibition of virus-induced cytotoxicity after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
1.3
nM
|
|
Antiviral activity against HIV1 3B infected in human MT4 cells assessed as inhibition of virus-induced cytotoxicity after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
1.288
nM
|
|
Journal : J Med Chem
Title : Exploiting the Tolerant Region I of the Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Binding Pocket: Discovery of Potent Diarylpyrimidine-Typed HIV-1 NNRTIs against Wild-Type and E138K Mutant Virus with Significantly Improved Water Solubility and Favorable Safety Profiles.
Year : 2019
Volume : 62
Issue : 4
First Page : 2083
Last Page : 2098
Authors : Huang B, Chen W, Zhao T, Li Z, Jiang X, Ginex T, Vílchez D, Luque FJ, Kang D, Gao P, Zhang J, Tian Y, Daelemans D, De Clercq E, Pannecouque C, Zhan P, Liu X.
Abstract : Diarylpyrimidine derivatives (DAPYs) exhibit robust anti-HIV-1 potency, although they have been compromised by E138K variant and severe side-effects and been suffering from poor water solubility. In the present work, hydrophilic morpholine or methylsulfonyl and sulfamide-substituted piperazine/piperidines were introduced into the right wing of DAPYs targeting the solvent-exposed tolerant region I. The anti-HIV-1 activities of 11c (EC50(WT) = 0.0035 μM, EC50(E138K) = 0.0075 μM) were the same as and 2-fold better than that of the lead etravirine against the wild-type and E138K mutant HIV-1, respectively, with a relative low cytotoxicity (CC50 ≥ 173 μM). Further test showed a significant improvement in the water solubility of 11c. Besides, 11c displayed no significant inhibition on main cytochrome P450 enzymes and exhibited no acute/subacute toxicities at doses of 2000 mg·kg-1/50 mg·kg-1 in mice. Taken together, we consider that 11c is a promising lead for further structural optimization.
|
Inhibition of HIV1 reverse transcriptase p66/p51 using poly(rA)/oligo(dT)16 as template/primer measured after 40 mins by pico-green based spectrofluorometric analysis
|
Human immunodeficiency virus 1
|
22.0
nM
|
|
Inhibition of HIV1 reverse transcriptase p66/p51 using poly(rA)/oligo(dT)16 as template/primer measured after 40 mins by pico-green based spectrofluorometric analysis
|
Human immunodeficiency virus 1
|
21.88
nM
|
|
Journal : J Med Chem
Title : Exploiting the Tolerant Region I of the Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Binding Pocket: Discovery of Potent Diarylpyrimidine-Typed HIV-1 NNRTIs against Wild-Type and E138K Mutant Virus with Significantly Improved Water Solubility and Favorable Safety Profiles.
Year : 2019
Volume : 62
Issue : 4
First Page : 2083
Last Page : 2098
Authors : Huang B, Chen W, Zhao T, Li Z, Jiang X, Ginex T, Vílchez D, Luque FJ, Kang D, Gao P, Zhang J, Tian Y, Daelemans D, De Clercq E, Pannecouque C, Zhan P, Liu X.
Abstract : Diarylpyrimidine derivatives (DAPYs) exhibit robust anti-HIV-1 potency, although they have been compromised by E138K variant and severe side-effects and been suffering from poor water solubility. In the present work, hydrophilic morpholine or methylsulfonyl and sulfamide-substituted piperazine/piperidines were introduced into the right wing of DAPYs targeting the solvent-exposed tolerant region I. The anti-HIV-1 activities of 11c (EC50(WT) = 0.0035 μM, EC50(E138K) = 0.0075 μM) were the same as and 2-fold better than that of the lead etravirine against the wild-type and E138K mutant HIV-1, respectively, with a relative low cytotoxicity (CC50 ≥ 173 μM). Further test showed a significant improvement in the water solubility of 11c. Besides, 11c displayed no significant inhibition on main cytochrome P450 enzymes and exhibited no acute/subacute toxicities at doses of 2000 mg·kg-1/50 mg·kg-1 in mice. Taken together, we consider that 11c is a promising lead for further structural optimization.
|
Inhibition of human ERG
|
Homo sapiens
|
500.0
nM
|
|
Journal : J Med Chem
Title : Discovery and Characterization of Fluorine-Substituted Diarylpyrimidine Derivatives as Novel HIV-1 NNRTIs with Highly Improved Resistance Profiles and Low Activity for the hERG Ion Channel.
Year : 2020
Volume : 63
Issue : 3
First Page : 1298
Last Page : 1312
Authors : Kang D, Ruiz FX, Feng D, Pilch A, Zhao T, Wei F, Wang Z, Sun Y, Fang Z, De Clercq E, Pannecouque C, Arnold E, Liu X, Zhan P.
Abstract : Our previous efforts have led to the development of two potent NNRTIs, K-5a2 and 25a, exhibiting effective anti-HIV-1 potency and resistance profiles compared with etravirine. However, both inhibitors suffered from potent hERG inhibition and short half-life. In this article, with K-5a2 and etravirine as leads, series of novel fluorine-substituted diarylpyrimidine derivatives were designed via molecular hybridization and bioisosterism strategies. The results indicated 24b was the most active inhibitor, exhibiting broad-spectrum activity (EC50 = 3.60-21.5 nM) against resistant strains, significantly lower cytotoxicity (CC50= 155 μM), and reduced hERG inhibition (IC50 > 30 μM). Crystallographic studies confirmed the binding of 24b and the role of the fluorine atom, as well as optimal contacts of a nitrile group with the main-chain carbonyl group of H235. Furthermore, 24b showed longer half-life and favorable safety properties. All the results demonstrated that 24b has significant promise in circumventing drug resistance as an anti-HIV-1 candidate.
|
Inhibition of recombinant HIV1 reverse transcriptase p66/p51 Y181C mutant expressed in Escherichia coli BL21 (DE3) pLysS cells preincubated followed by primer/template addition and measured after 30 mins by picogreen dye-based fluorescence assay
|
Human immunodeficiency virus 1
|
0.68
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Molecular and cellular studies evaluating a potent 2-cyanoindolizine catechol diether NNRTI targeting wildtype and Y181C mutant HIV-1 reverse transcriptase.
Year : 2019
Volume : 29
Issue : 16
First Page : 2182
Last Page : 2188
Authors : Sasaki T, Gannam ZTK, Kudalkar SN, Frey KM, Lee WG, Spasov KA, Jorgensen WL, Anderson KS.
Abstract : The development of efficacious NNRTIs for HIV/AIDS therapy is commonly met with the emergence of drug resistant strains, including the Y181C variant. Using a computationally-guided approach, we synthesized the catechol diether series of NNRTIs, which display sub-nanomolar potency in cellular assays. Among the most potent were a series of 2-cyanoindolizine substituted catechol diethers, including Compound 1. We present here a thorough evaluation of this compound, including biochemical, cellular, and structural studies. The compound demonstrates low nanomolar potency against both WT and Y181C HIV-1 RT in in vitro and cellular assays. Our crystal structures of both the wildtype and mutant forms of RT in complex with Compound 1 allow the interrogation of this compound's features that allow it to maintain strong efficacy against the drug resistant mutant. Among these are compensatory shifts in the NNRTI binding pocket, persistence of multiple hydrogen bonds, and van der Waals contacts throughout the binding site. Further, the fluorine at the C6 position of the indolizine moiety makes multiple favorable interactions with both RT forms. The present study highlights the indolizine-substituted catechol diether class of NNRTIs as promising therapeutic candidates possessing optimal pharmacological properties and significant potency against multiple RT variants.
|
Antiviral activity against wild-type HIV1 NL4-3 infected in human MT2 cells measured 48 hrs post-infection by MTT assay
|
Human immunodeficiency virus 1
|
0.67
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Molecular and cellular studies evaluating a potent 2-cyanoindolizine catechol diether NNRTI targeting wildtype and Y181C mutant HIV-1 reverse transcriptase.
Year : 2019
Volume : 29
Issue : 16
First Page : 2182
Last Page : 2188
Authors : Sasaki T, Gannam ZTK, Kudalkar SN, Frey KM, Lee WG, Spasov KA, Jorgensen WL, Anderson KS.
Abstract : The development of efficacious NNRTIs for HIV/AIDS therapy is commonly met with the emergence of drug resistant strains, including the Y181C variant. Using a computationally-guided approach, we synthesized the catechol diether series of NNRTIs, which display sub-nanomolar potency in cellular assays. Among the most potent were a series of 2-cyanoindolizine substituted catechol diethers, including Compound 1. We present here a thorough evaluation of this compound, including biochemical, cellular, and structural studies. The compound demonstrates low nanomolar potency against both WT and Y181C HIV-1 RT in in vitro and cellular assays. Our crystal structures of both the wildtype and mutant forms of RT in complex with Compound 1 allow the interrogation of this compound's features that allow it to maintain strong efficacy against the drug resistant mutant. Among these are compensatory shifts in the NNRTI binding pocket, persistence of multiple hydrogen bonds, and van der Waals contacts throughout the binding site. Further, the fluorine at the C6 position of the indolizine moiety makes multiple favorable interactions with both RT forms. The present study highlights the indolizine-substituted catechol diether class of NNRTIs as promising therapeutic candidates possessing optimal pharmacological properties and significant potency against multiple RT variants.
|
Antiviral activity against HIV1 NL4-3 harboring Y181C mutant infected in human MT2 cells measured 48 hrs post-infection by MTT assay
|
Human immunodeficiency virus 1
|
0.65
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Molecular and cellular studies evaluating a potent 2-cyanoindolizine catechol diether NNRTI targeting wildtype and Y181C mutant HIV-1 reverse transcriptase.
Year : 2019
Volume : 29
Issue : 16
First Page : 2182
Last Page : 2188
Authors : Sasaki T, Gannam ZTK, Kudalkar SN, Frey KM, Lee WG, Spasov KA, Jorgensen WL, Anderson KS.
Abstract : The development of efficacious NNRTIs for HIV/AIDS therapy is commonly met with the emergence of drug resistant strains, including the Y181C variant. Using a computationally-guided approach, we synthesized the catechol diether series of NNRTIs, which display sub-nanomolar potency in cellular assays. Among the most potent were a series of 2-cyanoindolizine substituted catechol diethers, including Compound 1. We present here a thorough evaluation of this compound, including biochemical, cellular, and structural studies. The compound demonstrates low nanomolar potency against both WT and Y181C HIV-1 RT in in vitro and cellular assays. Our crystal structures of both the wildtype and mutant forms of RT in complex with Compound 1 allow the interrogation of this compound's features that allow it to maintain strong efficacy against the drug resistant mutant. Among these are compensatory shifts in the NNRTI binding pocket, persistence of multiple hydrogen bonds, and van der Waals contacts throughout the binding site. Further, the fluorine at the C6 position of the indolizine moiety makes multiple favorable interactions with both RT forms. The present study highlights the indolizine-substituted catechol diether class of NNRTIs as promising therapeutic candidates possessing optimal pharmacological properties and significant potency against multiple RT variants.
|
Antiviral activity against wild type HIV1 NL4-3
|
Human immunodeficiency virus 1
|
0.9
nM
|
|
Journal : J Med Chem
Title : Discovery and Structure-Based Optimization of 2-Ureidothiophene-3-carboxylic Acids as Dual Bacterial RNA Polymerase and Viral Reverse Transcriptase Inhibitors.
Year : 2016
Volume : 59
Issue : 15
First Page : 7212
Last Page : 7222
Authors : Elgaher WA, Sharma KK, Haupenthal J, Saladini F, Pires M, Real E, Mély Y, Hartmann RW.
Abstract : We are concerned with the development of novel anti-infectives with dual antibacterial and antiretroviral activities for MRSA/HIV-1 co-infection. To achieve this goal, we exploited for the first time the mechanistic function similarity between the bacterial RNA polymerase (RNAP) "switch region" and the viral non-nucleoside reverse transcriptase inhibitor (NNRTI) binding site. Starting from our previously discovered RNAP inhibitors, we managed to develop potent RT inhibitors effective against several resistant HIV-1 strains with maintained or enhanced RNAP inhibitory properties following a structure-based design approach. A quantitative structure-activity relationship (QSAR) analysis revealed distinct molecular features necessary for RT inhibition. Furthermore, mode of action (MoA) studies revealed that these compounds inhibit RT noncompetitively, through a new mechanism via closing of the RT clamp. In addition, the novel RNAP/RT inhibitors are characterized by a potent antibacterial activity against S. aureus and in cellulo antiretroviral activity against NNRTI-resistant strains. In HeLa and HEK 293 cells, the compounds showed only marginal cytotoxicity.
|
Antiviral activity against HIV1 3B infected in human MT2 cells assessed as protection against viral infection by MTT method
|
Human immunodeficiency virus 1
|
0.67
nM
|
|
Journal : Bioorg Med Chem
Title : Computer-aided discovery of anti-HIV agents.
Year : 2016
Volume : 24
Issue : 20
First Page : 4768
Last Page : 4778
Authors : Jorgensen WL.
Abstract : A review is provided on efforts in our laboratory over the last decade to discover anti-HIV agents. The work has focused on computer-aided design and synthesis of non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) with collaborative efforts on biological assaying and protein crystallography. Numerous design issues were successfully addressed including the need for potency against a wide range of viral variants, good aqueous solubility, and avoidance of electrophilic substructures. Computational methods including docking, de novo design, and free-energy perturbation (FEP) calculations made essential contributions. The result is novel NNRTIs with picomolar and low-nanomolar activities against wild-type HIV-1 and key variants that also show much improved solubility and lower cytotoxicity than recently approved drugs in the class.
|
Antiviral activity against HIV1 3B harboring reverse transcriptase Y181C mutant infected in human MT2 cells assessed as protection against viral infection by MTT method
|
Human immunodeficiency virus 1
|
0.65
nM
|
|
Journal : Bioorg Med Chem
Title : Computer-aided discovery of anti-HIV agents.
Year : 2016
Volume : 24
Issue : 20
First Page : 4768
Last Page : 4778
Authors : Jorgensen WL.
Abstract : A review is provided on efforts in our laboratory over the last decade to discover anti-HIV agents. The work has focused on computer-aided design and synthesis of non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) with collaborative efforts on biological assaying and protein crystallography. Numerous design issues were successfully addressed including the need for potency against a wide range of viral variants, good aqueous solubility, and avoidance of electrophilic substructures. Computational methods including docking, de novo design, and free-energy perturbation (FEP) calculations made essential contributions. The result is novel NNRTIs with picomolar and low-nanomolar activities against wild-type HIV-1 and key variants that also show much improved solubility and lower cytotoxicity than recently approved drugs in the class.
|
Antiviral activity against HIV1 3B harboring reverse transcriptase K103N/Y181C double mutant infected in human MT2 cells assessed as protection against viral infection by MTT method
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : Bioorg Med Chem
Title : Computer-aided discovery of anti-HIV agents.
Year : 2016
Volume : 24
Issue : 20
First Page : 4768
Last Page : 4778
Authors : Jorgensen WL.
Abstract : A review is provided on efforts in our laboratory over the last decade to discover anti-HIV agents. The work has focused on computer-aided design and synthesis of non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) with collaborative efforts on biological assaying and protein crystallography. Numerous design issues were successfully addressed including the need for potency against a wide range of viral variants, good aqueous solubility, and avoidance of electrophilic substructures. Computational methods including docking, de novo design, and free-energy perturbation (FEP) calculations made essential contributions. The result is novel NNRTIs with picomolar and low-nanomolar activities against wild-type HIV-1 and key variants that also show much improved solubility and lower cytotoxicity than recently approved drugs in the class.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
1.34
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
5.68
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-36.34
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
1.73
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
2.92
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.3
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
2.92
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
1.73
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.3
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Covalent inhibition of recombinant wild type HIV-1 reverse transcriptase using poly(rA)350/oligo(dT)16 as template/primer preincubated followed by substrate addition measured after 1 hr by pico-green reagent based fluorescence analysis
|
Human immunodeficiency virus 1
|
38.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Covalent Inhibition of Wild-Type HIV-1 Reverse Transcriptase Using a Fluorosulfate Warhead.
Year : 2021
Volume : 12
Issue : 2
First Page : 249
Last Page : 255
Authors : Ippolito JA,Niu H,Bertoletti N,Carter ZJ,Jin S,Spasov KA,Cisneros JA,Valhondo M,Cutrona KJ,Anderson KS,Jorgensen WL
Abstract : Covalent inhibitors of wild-type HIV-1 reverse transcriptase (CRTIs) are reported. Three compounds derived from catechol diether non-nucleoside inhibitors (NNRTIs) with addition of a fluorosulfate warhead are demonstrated to covalently modify Tyr181 of HIV-RT. X-ray crystal structures for complexes of the CRTIs with the enzyme are provided, which fully demonstrate the covalent attachment, and confirmation is provided by appropriate mass shifts in ESI-TOF mass spectra. The three CRTIs and six noncovalent analogues are found to be potent inhibitors with both IC values for in vitro inhibition of WT RT and EC values for cytopathic protection of HIV-1-infected human T-cells in the 5-320 nM range.
|
Antiviral activity against HIV1 3B infected in human MT4 cells assessed as protection against virus-induced cytopathic effect incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
0.67
nM
|
|
Journal : ACS Med Chem Lett
Title : Covalent Inhibition of Wild-Type HIV-1 Reverse Transcriptase Using a Fluorosulfate Warhead.
Year : 2021
Volume : 12
Issue : 2
First Page : 249
Last Page : 255
Authors : Ippolito JA,Niu H,Bertoletti N,Carter ZJ,Jin S,Spasov KA,Cisneros JA,Valhondo M,Cutrona KJ,Anderson KS,Jorgensen WL
Abstract : Covalent inhibitors of wild-type HIV-1 reverse transcriptase (CRTIs) are reported. Three compounds derived from catechol diether non-nucleoside inhibitors (NNRTIs) with addition of a fluorosulfate warhead are demonstrated to covalently modify Tyr181 of HIV-RT. X-ray crystal structures for complexes of the CRTIs with the enzyme are provided, which fully demonstrate the covalent attachment, and confirmation is provided by appropriate mass shifts in ESI-TOF mass spectra. The three CRTIs and six noncovalent analogues are found to be potent inhibitors with both IC values for in vitro inhibition of WT RT and EC values for cytopathic protection of HIV-1-infected human T-cells in the 5-320 nM range.
|
Antiviral activity against HIV-3B infected in human MT-4 cells assessed as reduction in virus-induced cytopathic effect incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
10.0
nM
|
|
Journal : Bioorg Med Chem
Title : Novel indolylarylsulfone derivatives as covalent HIV-1 reverse transcriptase inhibitors specifically targeting the drug-resistant mutant Y181C.
Year : 2021
Volume : 30
First Page : 115927
Last Page : 115927
Authors : Gao P,Song S,Frutos-Beltrán E,Li W,Sun B,Kang D,Zou J,Zhang J,Pannecouque C,De Clercq E,Menéndez-Arias L,Zhan P,Liu X
Abstract : Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are widely used in combination therapies against HIV-1. However, emergent and transmitted drug resistance compromise their efficacy in the clinical setting. Y181C is selected in patients receiving nevirapine, etravirine and rilpivirine, and together with K103N is the most prevalent NNRTI-associated mutation in HIV-infected patients. Herein, we report on the design, synthesis and biological evaluation of a novel series of indolylarylsulfones bearing acrylamide or ethylene sulfonamide reactive groups as warheads to inactivate Cys181-containing HIV-1 RT via a Michael addition reaction. Compounds I-7 and I-9 demonstrated higher selectivity towards the Y181C mutant than against the wild-type RT, in nucleotide incorporation inhibition assays. The larger size of the NNRTI binding pocket in the mutant enzyme facilitates a better fit for the active compounds, while stacking interactions with Phe227 and Pro236 contribute to inhibitor binding. Mass spectrometry data were consistent with the covalent modification of the RT, although off-target reactivity constitutes a major limitation for further development of the described inhibitors.
|
Antiviral activity against HIV-1 infected in human MT-4 cells assessed as reduction in virus-induced cytopathic effect incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
|
Antiviral activity against HIV1 3B infected in human MT4 cells assessed as reduction in virus-induced cytopathogenic effect by MTT assay
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
|
Antiviral activity against HIV1 RES056 infected in human MT4 cells assessed as reduction in virus-induced cytopathogenic effect by MTT assay
|
Human immunodeficiency virus 1
|
10.7
nM
|
|
|
Antiviral activity against HIV1 harboring L100I mutant infected in human MT4 cells assessed as reduction in virus-induced cytopathogenic effect by MTT assay
|
Human immunodeficiency virus 1
|
1.54
nM
|
|
|
Antiviral activity against HIV1 harboring K103N mutant infected in human MT4 cells assessed as reduction in virus-induced cytopathogenic effect by MTT assay
|
Human immunodeficiency virus 1
|
1.31
nM
|
|
|
Antiviral activity against wild type HIV1 harboring Y181C mutant infected in human MT4 cells assessed as reduction in virus-induced cytopathogenic effect by MTT assay
|
Human immunodeficiency virus 1
|
79.4
nM
|
|
|
Antiviral activity against wild type HIV1 harboring Y188L mutant infected in human MT4 cells assessed as reduction in virus-induced cytopathogenic effect by MTT assay
|
Human immunodeficiency virus 1
|
79.4
nM
|
|
|
Antiviral activity against wild type HIV1 harboring E138K mutant infected in human MT4 cells assessed as reduction in virus-induced cytopathogenic effect by MTT assay
|
Human immunodeficiency virus 1
|
5.75
nM
|
|
|
Antiviral activity against HIV1 harboring F227L/V106A mutant infected in human MT4 cells assessed as reduction in virus-induced cytopathogenic effect by MTT assay
|
Human immunodeficiency virus 1
|
81.6
nM
|
|
|
Inhibition of wild type HIV1 reverse transcriptase assessed as reduction in biotin-dUTP incorporation into protein incubated for 1 hrs by ELISA
|
Human immunodeficiency virus 1
|
15.0
nM
|
|
|
Inhibition of CYP2C9 in human liver microsomes using diclofenac as substrate in presence of NADPH incubated for 10 mins by LC-MS/MS analysis
|
Homo sapiens
|
346.0
nM
|
|
|
Inhibition of CYP2C19 in human liver microsomes using S-mephenytoin as substrate in presence of NADPH incubated for 10 mins by LC-MS/MS analysis
|
Homo sapiens
|
335.0
nM
|
|
|
Inhibition of human ERG expressed in CHO cells by manual patch clamp technique
|
Homo sapiens
|
500.0
nM
|
|
|
Antiviral activity against HIV1 3B infected in human MT4 cells assessed as protection against virus-induced cytopathic effect incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
|
Antiviral activity against HIV1 RES056 infected in human MT4 cells assessed as protection against virus-induced cytopathic effect incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
10.7
nM
|
|
|
Inhibition of wild type HIV1 p66/p51 reverse transcriptase using poly(rA) as template, oligo(dT)16 as primer and RNA/DNA as substrate measured after 40 mins by PICOGreen-dye based spectrofluorimetry analysis
|
Human immunodeficiency virus 1
|
22.0
nM
|
|
|
Antiviral activity against HIV-1 strain IIIB infected in human MT4 cells assessed as protection against virus-induced cytopathicity after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
|
Antiviral activity against NNRTI-resistant HIV-1 RES056 harboring RT K103N/Y181C mutant infected in human MT4 cells assessed as protection against virus-induced cytopathogenicity after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
10.7
nM
|
|
|
Antiviral activity against HIV-1 harboring RT L100I mutant infected in human MT4 cells assessed as protection against virus-induced cytopathogenicity after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
1.54
nM
|
|
|
Antiviral activity against HIV-1 harboring RT K103N mutant infected in human MT4 cells assessed as protection against virus-induced cytopathogenicity after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
1.31
nM
|
|
|
Antiviral activity against HIV-1 harboring RT Y181C mutant infected in human MT4 cells assessed as protection against virus-induced cytopathogenicity after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
4.73
nM
|
|
|
Antiviral activity against HIV-1 harboring RT Y188L mutant infected in human MT4 cells assessed as protection against virus-induced cytopathogenicity after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
79.4
nM
|
|
|
Antiviral activity against HIV-1 harboring RT E138K mutant infected in human MT4 cells assessed as protection against virus-induced cytopathogenicity after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
5.75
nM
|
|
|
Antiviral activity against HIV-1 harboring RT F227L/V106A mutant infected in human MT4 cells assessed as protection against virus-induced cytopathogenicity after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
81.6
nM
|
|
|
Antiviral activity against HIV1 IIIB infected human MT4 cells assessed as protection against virus-induced cytopathic effect by MTT assay
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
|
Inhibition of human CYP2C9 using tolbutamide as substrate in presence of NADPH incubated for 15 to 45 mins
|
Homo sapiens
|
346.0
nM
|
|
|
Inhibition of human CYP2C19 using S-mephenytoin as substrate in presence of NADPH incubated for 15 to 45 mins
|
Homo sapiens
|
335.0
nM
|
|
|
Antiviral activity against HIV-1 IIIB infected in human MT4 cells assessed as protection against virus-induced cytotoxicity incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
|
Antiviral activity against HIV-1 IIIB harboring K103N/Y181C double mutant infected in human MT4 cells assessed as protection against virus-induced cytotoxicity incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
10.7
nM
|
|
|
Antiviral activity against HIV1 L1001 infected in human MT4 cells assessed as protection against virus-induced cytopathic effect incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
1.54
nM
|
|
|
Antiviral activity against HIV-1 harboring reverse transcriptase K103N mutant infected in human MT4 cells assessed as protection against virus-induced cytopathic effect incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
1.31
nM
|
|
|
Antiviral activity against HIV-1 harboring reverse transcriptase Y181C mutant infected in human MT4 cells assessed as protection against virus-induced cytopathic effect incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
4.73
nM
|
|
|
Antiviral activity against HIV-1 harboring reverse transcriptase Y188L mutant infected in human MT4 cells assessed as protection against virus-induced cytopathic effect incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
79.4
nM
|
|
|
Antiviral activity against HIV-1 harboring reverse transcriptase E138K mutant infected in human MT4 cells assessed as protection against virus-induced cytopathic effect incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
5.75
nM
|
|
|
Antiviral activity against HIV-1 harboring reverse transcriptase F227L/V106A mutant infected in human MT4 cells assessed as protection against virus-induced cytopathic effect incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
81.6
nM
|
|
|
Inhibition of recombinant wild type p66/p51 HIV1 reverse transcriptase incubated for 40 mins by picogreen dye-based spectrofluorometric analysis
|
Human immunodeficiency virus 1
|
15.0
nM
|
|
