|
Antiviral activity against HCV infected in human clone A cells assessed as inhibition of cellular rRNA replication at 50 uM
|
Hepatitis C virus
|
0.09
%
|
|
Journal : J. Med. Chem.
Title : Discovery of a β-d-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus.
Year : 2010
Volume : 53
Issue : 19
First Page : 7202
Last Page : 7218
Authors : Sofia MJ, Bao D, Chang W, Du J, Nagarathnam D, Rachakonda S, Reddy PG, Ross BS, Wang P, Zhang HR, Bansal S, Espiritu C, Keilman M, Lam AM, Steuer HM, Niu C, Otto MJ, Furman PA.
Abstract : Hepatitis C virus (HCV) is a global health problem requiring novel approaches for effective treatment of this disease. The HCV NS5B polymerase has been demonstrated to be a viable target for the development of HCV therapies. β-d-2'-Deoxy-2'-α-fluoro-2'-β-C-methyl nucleosides are selective inhibitors of the HCV NS5B polymerase and have demonstrated potent activity in the clinic. Phosphoramidate prodrugs of the 5'-phosphate derivative of the β-d-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine nucleoside were prepared and showed significant potency in the HCV subgenomic replicon assay (<1 μM) and produced high levels of triphosphate 6 in primary hepatocytes and in the livers of rats, dogs, and monkeys when administered in vivo. The single diastereomer 51 of diastereomeric mixture 14 was crystallized, and an X-ray structure was determined establishing the phosphoramidate stereochemistry as Sp, thus correlating for the first time the stereochemistry of a phosphoramidate prodrug with biological activity. 51 (PSI-7977) was selected as a clinical development candidate.
|
Antiviral activity against Hepatitis C virus genotype 1b in human Huh7-luc clone ET replicon cells assessed as inhibition of replicon replication after 3 days by luciferase assay
|
Hepatitis C virus subtype 1b
|
254.0
nM
|
|
Journal : J. Med. Chem.
Title : Nucleotide prodrugs of 2'-deoxy-2'-spirooxetane ribonucleosides as novel inhibitors of the HCV NS5B polymerase.
Year : 2014
Volume : 57
Issue : 5
First Page : 1836
Last Page : 1844
Authors : Jonckers TH, Vandyck K, Vandekerckhove L, Hu L, Tahri A, Van Hoof S, Lin TI, Vijgen L, Berke JM, Lachau-Durand S, Stoops B, Leclercq L, Fanning G, Samuelsson B, Nilsson M, Rosenquist Å, Simmen K, Raboisson P.
Abstract : The limited efficacy, in particular against the genotype 1 virus, as well as the variety of side effects associated with the current therapy for hepatitis C virus (HCV) infection necessitates more efficacious drugs. We found that phosphoramidate prodrugs of 2'-deoxy-2'-spirooxetane ribonucleosides form a novel class of HCV NS5B RNA-dependent RNA polymerase inhibitors, displaying EC50 values ranging from 0.2 to >98 μM, measured in the Huh7-replicon cell line, with no apparent cytotoxicity (CC50 > 98.4 μM). Confirming recent findings, the 2'-spirooxetane moiety was identified as a novel structural motif in the field of anti-HCV nucleosides. A convenient synthesis was developed that enabled the synthesis of a broad set of nucleotide prodrugs with varying substitution patterns. Extensive formation of the triphosphate metabolite was observed in both rat and human hepatocyte cultures. In addition, after oral dosing of several phosphoramidate derivatives of compound 21 to rats, substantial hepatic levels of the active triphosphate metabolite were found.
|
Antiviral activity against Hepatitis C virus infected in African green monkey OR6 cells after 72 hrs by luciferase reporter gene assay
|
Hepatitis C virus
|
140.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of 3',4'-difluoro-3'-deoxyribonucleosides and its evaluation of the biological activities: discovery of a novel type of anti-HCV agent 3',4'-difluorocordycepin.
Year : 2014
Volume : 22
Issue : 21
First Page : 6174
Last Page : 6182
Authors : Shimada H, Haraguchi K, Hotta K, Miyaike T, Kitagawa Y, Tanaka H, Kaneda R, Abe H, Shuto S, Mori K, Ueda Y, Kato N, Snoeck R, Andrei G, Balzarini J.
Abstract : Upon reacting 3',4'-unsaturated cytosine (8 and 9) and adenine nucleosides (13 and 14) with XeF(2)/BF3 · OEt(2), the respective novel 3',4'-difluoro-3'-deoxyribofuranosyl nucleosides (10-12 and 15-18) could be obtained. Formation of anti-adducts (11, 16 and 18) revealed that the fluorination involved oxonium ions as incipient intermediates. TBDMS-protected 3',4'-unsaturated adenosine provided the β-face adducts as sole stereoisomers whereas α-face-selectivity was observed with the TBDPS-protected adenosine 14. The evaluation of the novel 3'-deoxy-3',4'-difluororibofuranosylcytosine-(19-21) and adenine nucleosides (22-25) against antitumor and antiviral activities revealed that 3',4'-difluorocordycepin (24) was found to possess anti-HCV activity. The SI of 24 was comparable to that of the anti-HCV drug ribavirin. However, sofosbuvir, FDA-approved novel anti-HCV drug, showed better SI value. Our finding revealed that the introduction of the fluoro-substituent into the 4'-position of cordycepin derivatives decreased the cytotoxicity to the host cell with retention of the antiviral activity.
|
Antiviral activity against HCV JFH-1 infected in human HuH7.5.1 cells after 48 hrs by luciferase reporter gene assay
|
Hepatitis C virus JFH-1
|
120.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of 2'-α-C-Methyl-2'-β-C-fluorouridine Phosphoramidate Prodrugs as Inhibitors of Hepatitis C Virus.
Year : 2016
Volume : 7
Issue : 12
First Page : 1197
Last Page : 1201
Authors : Zeng D, Zhang R, Nie Q, Cao L, Shang L, Yin Z.
Abstract : 2'-α-C-Methyl-2'-β-C-fluorouridine and its phosphoramidate prodrugs were synthesized and evaluated for their inhibitory activity against HCV. The structure-activity relationship analysis of the phosphoramidate moiety found that 17m, 17q, and 17r exhibit potent activities against HCV, with EC50 values of 1.82 ± 0.19, 0.88 ± 0.12, and 2.24 ± 0.22 μM, respectively. The docking study revealed that the recognition of the 2'-β-F by Arg158, 3'-OH by N291, and the Watson-Crick pairing with the template allowed 23 to form the in-line conformation necessary for its incorporation into the viral RNA chain.
|
Inhibition of wild type NS5B in HCV genotype 1b replicon expressed in human HuH7 cells after 72 hrs by bright Glo-luciferase reporter gene assay
|
Hepatitis C virus subtype 1b
|
150.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel Nucleotide Prodrugs with Improved Potency Against HCV Variants Carrying NS5B S282T Mutation.
Year : 2017
Volume : 60
Issue : 14
First Page : 6077
Last Page : 6088
Authors : Zhen L, Dai L, Wen X, Yao L, Jin X, Yang XW, Zhao W, Yu SQ, Yuan H, Wang G, Sun H.
Abstract : Resistant HCV variants carrying NS5B S282T mutation confer reduced sensitivity to sofosbuvir, the sole marketed NS5B polymerase inhibitor. On the basis of the finding that 2'-α-F-2'-β-C-methylcytidine 5'-triphosphate (8) was more potent than sofosbuvir's active metabolite on inhibition of both wild-type and S282T mutant polymerase, a dual-prodrug approach has been established. Twenty-nine phosphoramidates with N4-modified cytosine were designed, synthesized, and evaluated for anti-HCV activity. The results showed that compounds 4c-4e and 4m (EC50 = 0.19-0.25 μM) exhibited comparable potency to that of sofosbuvir (EC50 = 0.15 μM) on inhibition of wild-type replicons. Notably, 4c (EC50 = 0.366 μM) was 1.5-fold more potent than sofosbuvir (EC50 = 0.589 μM) on inhibition of S282T mutant replicons. In vitro metabolic studies disclosed the possible metabolic pathways of 4c. The toxicity study results indicated a good safety profile of 4c. Together, 4c-4e and 4m hold promise for drug development for the treatment of HCV infection, especially the resistant variants with NS5B S282T mutation.
|
Inhibition of NS5B S282T mutant in HCV genotype 1b replicon expressed in human HuH7 cells after 72 hrs by bright Glo-luciferase reporter gene assay
|
Hepatitis C virus subtype 1b
|
589.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel Nucleotide Prodrugs with Improved Potency Against HCV Variants Carrying NS5B S282T Mutation.
Year : 2017
Volume : 60
Issue : 14
First Page : 6077
Last Page : 6088
Authors : Zhen L, Dai L, Wen X, Yao L, Jin X, Yang XW, Zhao W, Yu SQ, Yuan H, Wang G, Sun H.
Abstract : Resistant HCV variants carrying NS5B S282T mutation confer reduced sensitivity to sofosbuvir, the sole marketed NS5B polymerase inhibitor. On the basis of the finding that 2'-α-F-2'-β-C-methylcytidine 5'-triphosphate (8) was more potent than sofosbuvir's active metabolite on inhibition of both wild-type and S282T mutant polymerase, a dual-prodrug approach has been established. Twenty-nine phosphoramidates with N4-modified cytosine were designed, synthesized, and evaluated for anti-HCV activity. The results showed that compounds 4c-4e and 4m (EC50 = 0.19-0.25 μM) exhibited comparable potency to that of sofosbuvir (EC50 = 0.15 μM) on inhibition of wild-type replicons. Notably, 4c (EC50 = 0.366 μM) was 1.5-fold more potent than sofosbuvir (EC50 = 0.589 μM) on inhibition of S282T mutant replicons. In vitro metabolic studies disclosed the possible metabolic pathways of 4c. The toxicity study results indicated a good safety profile of 4c. Together, 4c-4e and 4m hold promise for drug development for the treatment of HCV infection, especially the resistant variants with NS5B S282T mutation.
|
Antiviral activity against HCV genotype 1b harboring wild type NS5B infected in human HuH7 cells assessed as inhibition of viral RNA replication after 5 days by RT-PCR method
|
Hepatitis C virus subtype 1b
|
90.0
nM
|
|
Journal : J Med Chem
Title : 2'-Chloro,2'-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture.
Year : 2017
Volume : 60
Issue : 13
First Page : 5424
Last Page : 5437
Authors : Zhou S, Mahmoud S, Liu P, Zhou L, Ehteshami M, Bassit L, Tao S, Domaoal RA, Sari O, Schutter C, Amiralaei S, Khalil A, Ollinger Russell O, McBrayer T, Whitaker T, Abou-Taleb N, Amblard F, Coats SJ, Schinazi RF.
Abstract : Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a β-d-2'-Cl,2'-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate 16 in its 5'-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent.
|
Antiviral activity against HCV genotype 1a infected in human HuH7 cells assessed as inhibition of viral RNA replication after 96 hrs by RT-PCR method
|
Hepatitis C virus subtype 1a
|
60.0
nM
|
|
Journal : J Med Chem
Title : 2'-Chloro,2'-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture.
Year : 2017
Volume : 60
Issue : 13
First Page : 5424
Last Page : 5437
Authors : Zhou S, Mahmoud S, Liu P, Zhou L, Ehteshami M, Bassit L, Tao S, Domaoal RA, Sari O, Schutter C, Amiralaei S, Khalil A, Ollinger Russell O, McBrayer T, Whitaker T, Abou-Taleb N, Amblard F, Coats SJ, Schinazi RF.
Abstract : Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a β-d-2'-Cl,2'-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate 16 in its 5'-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent.
|
Antiviral activity against HCV genotype 1b infected in human HuH7 cells assessed as inhibition of viral RNA replication after 96 hrs by RT-PCR method
|
Hepatitis C virus subtype 1b
|
60.0
nM
|
|
Journal : J Med Chem
Title : 2'-Chloro,2'-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture.
Year : 2017
Volume : 60
Issue : 13
First Page : 5424
Last Page : 5437
Authors : Zhou S, Mahmoud S, Liu P, Zhou L, Ehteshami M, Bassit L, Tao S, Domaoal RA, Sari O, Schutter C, Amiralaei S, Khalil A, Ollinger Russell O, McBrayer T, Whitaker T, Abou-Taleb N, Amblard F, Coats SJ, Schinazi RF.
Abstract : Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a β-d-2'-Cl,2'-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate 16 in its 5'-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent.
|
Antiviral activity against HCV genotype 2a/k infected in human HuH7 cells assessed as inhibition of viral RNA replication after 96 hrs by RT-PCR method
|
Hepatitis C virus subtype 2a
|
20.0
nM
|
|
Journal : J Med Chem
Title : 2'-Chloro,2'-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture.
Year : 2017
Volume : 60
Issue : 13
First Page : 5424
Last Page : 5437
Authors : Zhou S, Mahmoud S, Liu P, Zhou L, Ehteshami M, Bassit L, Tao S, Domaoal RA, Sari O, Schutter C, Amiralaei S, Khalil A, Ollinger Russell O, McBrayer T, Whitaker T, Abou-Taleb N, Amblard F, Coats SJ, Schinazi RF.
Abstract : Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a β-d-2'-Cl,2'-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate 16 in its 5'-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent.
|
Antiviral activity against HCV genotype 2b infected in human HuH7 cells assessed as inhibition of viral RNA replication after 96 hrs by RT-PCR method
|
Hepatitis C virus subtype 2b
|
40.0
nM
|
|
Journal : J Med Chem
Title : 2'-Chloro,2'-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture.
Year : 2017
Volume : 60
Issue : 13
First Page : 5424
Last Page : 5437
Authors : Zhou S, Mahmoud S, Liu P, Zhou L, Ehteshami M, Bassit L, Tao S, Domaoal RA, Sari O, Schutter C, Amiralaei S, Khalil A, Ollinger Russell O, McBrayer T, Whitaker T, Abou-Taleb N, Amblard F, Coats SJ, Schinazi RF.
Abstract : Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a β-d-2'-Cl,2'-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate 16 in its 5'-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent.
|
Antiviral activity against HCV genotype 3a infected in human HuH7 cells assessed as inhibition of viral RNA replication after 96 hrs by RT-PCR method
|
Hepatitis C virus subtype 3a
|
90.0
nM
|
|
Journal : J Med Chem
Title : 2'-Chloro,2'-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture.
Year : 2017
Volume : 60
Issue : 13
First Page : 5424
Last Page : 5437
Authors : Zhou S, Mahmoud S, Liu P, Zhou L, Ehteshami M, Bassit L, Tao S, Domaoal RA, Sari O, Schutter C, Amiralaei S, Khalil A, Ollinger Russell O, McBrayer T, Whitaker T, Abou-Taleb N, Amblard F, Coats SJ, Schinazi RF.
Abstract : Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a β-d-2'-Cl,2'-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate 16 in its 5'-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent.
|
Antiviral activity against HCV genotype 4 infected in human HuH7 cells assessed as inhibition of viral RNA replication after 96 hrs by RT-PCR method
|
Hepatitis C virus genotype 4
|
70.0
nM
|
|
Journal : J Med Chem
Title : 2'-Chloro,2'-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture.
Year : 2017
Volume : 60
Issue : 13
First Page : 5424
Last Page : 5437
Authors : Zhou S, Mahmoud S, Liu P, Zhou L, Ehteshami M, Bassit L, Tao S, Domaoal RA, Sari O, Schutter C, Amiralaei S, Khalil A, Ollinger Russell O, McBrayer T, Whitaker T, Abou-Taleb N, Amblard F, Coats SJ, Schinazi RF.
Abstract : Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a β-d-2'-Cl,2'-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate 16 in its 5'-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent.
|
Mitochondrial toxicity in human HepG2 cells assessed as inhibition of cytochrome c oxidase subunit 2 DNA levels at 10 uM measured on day 14 by RT-PCR method relative to nuclear beta-actin DNA levels
|
Homo sapiens
|
1.0
%
|
|
Journal : J Med Chem
Title : 2'-Chloro,2'-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture.
Year : 2017
Volume : 60
Issue : 13
First Page : 5424
Last Page : 5437
Authors : Zhou S, Mahmoud S, Liu P, Zhou L, Ehteshami M, Bassit L, Tao S, Domaoal RA, Sari O, Schutter C, Amiralaei S, Khalil A, Ollinger Russell O, McBrayer T, Whitaker T, Abou-Taleb N, Amblard F, Coats SJ, Schinazi RF.
Abstract : Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a β-d-2'-Cl,2'-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate 16 in its 5'-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent.
|
Antiviral activity against HCV genotype 1b harboring NS5B S282T mutant infected in human HuH7 cells assessed as inhibition of viral RNA replication after 4 days by luciferase reporter gene assay
|
Hepatitis C virus subtype 1b
|
400.0
nM
|
|
Journal : J Med Chem
Title : 2'-Chloro,2'-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture.
Year : 2017
Volume : 60
Issue : 13
First Page : 5424
Last Page : 5437
Authors : Zhou S, Mahmoud S, Liu P, Zhou L, Ehteshami M, Bassit L, Tao S, Domaoal RA, Sari O, Schutter C, Amiralaei S, Khalil A, Ollinger Russell O, McBrayer T, Whitaker T, Abou-Taleb N, Amblard F, Coats SJ, Schinazi RF.
Abstract : Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a β-d-2'-Cl,2'-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate 16 in its 5'-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent.
|
Cytotoxicity against human HepG2 cells assessed as inhibition of nuclear DNA levels at 10 uM measured on day 14 by RT-PCR method relative to nuclear beta-actin DNA levels
|
Homo sapiens
|
7.3
%
|
|
Journal : J Med Chem
Title : 2'-Chloro,2'-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture.
Year : 2017
Volume : 60
Issue : 13
First Page : 5424
Last Page : 5437
Authors : Zhou S, Mahmoud S, Liu P, Zhou L, Ehteshami M, Bassit L, Tao S, Domaoal RA, Sari O, Schutter C, Amiralaei S, Khalil A, Ollinger Russell O, McBrayer T, Whitaker T, Abou-Taleb N, Amblard F, Coats SJ, Schinazi RF.
Abstract : Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a β-d-2'-Cl,2'-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate 16 in its 5'-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent.
|
Mitochondrial toxicity in human HepG2 cells assessed as inhibition of cytochrome c oxidase subunit 2 DNA levels at 50 uM measured on day 14 by RT-PCR method relative to nuclear beta-actin DNA levels
|
Homo sapiens
|
1.0
%
|
|
Journal : J Med Chem
Title : 2'-Chloro,2'-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture.
Year : 2017
Volume : 60
Issue : 13
First Page : 5424
Last Page : 5437
Authors : Zhou S, Mahmoud S, Liu P, Zhou L, Ehteshami M, Bassit L, Tao S, Domaoal RA, Sari O, Schutter C, Amiralaei S, Khalil A, Ollinger Russell O, McBrayer T, Whitaker T, Abou-Taleb N, Amblard F, Coats SJ, Schinazi RF.
Abstract : Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a β-d-2'-Cl,2'-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate 16 in its 5'-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent.
|
Cytotoxicity against human HepG2 cells assessed as inhibition of nuclear DNA levels at 50 uM measured on day 14 by RT-PCR method relative to nuclear beta-actin DNA levels
|
Homo sapiens
|
38.8
%
|
|
Journal : J Med Chem
Title : 2'-Chloro,2'-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture.
Year : 2017
Volume : 60
Issue : 13
First Page : 5424
Last Page : 5437
Authors : Zhou S, Mahmoud S, Liu P, Zhou L, Ehteshami M, Bassit L, Tao S, Domaoal RA, Sari O, Schutter C, Amiralaei S, Khalil A, Ollinger Russell O, McBrayer T, Whitaker T, Abou-Taleb N, Amblard F, Coats SJ, Schinazi RF.
Abstract : Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a β-d-2'-Cl,2'-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate 16 in its 5'-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent.
|
Mitochondrial toxicity in human HepG2 cells assessed as inhibition of cytochrome c oxidase subunit 2 DNA levels at 25 uM measured on day 14 by RT-PCR method relative to nuclear beta-actin DNA levels
|
Homo sapiens
|
1.0
%
|
|
Journal : J Med Chem
Title : 2'-Chloro,2'-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture.
Year : 2017
Volume : 60
Issue : 13
First Page : 5424
Last Page : 5437
Authors : Zhou S, Mahmoud S, Liu P, Zhou L, Ehteshami M, Bassit L, Tao S, Domaoal RA, Sari O, Schutter C, Amiralaei S, Khalil A, Ollinger Russell O, McBrayer T, Whitaker T, Abou-Taleb N, Amblard F, Coats SJ, Schinazi RF.
Abstract : Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a β-d-2'-Cl,2'-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate 16 in its 5'-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent.
|
Cytotoxicity against human HepG2 cells assessed as inhibition of nuclear DNA levels at 25 uM measured on day 14 by RT-PCR method relative to nuclear beta-actin DNA levels
|
Homo sapiens
|
38.3
%
|
|
Journal : J Med Chem
Title : 2'-Chloro,2'-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture.
Year : 2017
Volume : 60
Issue : 13
First Page : 5424
Last Page : 5437
Authors : Zhou S, Mahmoud S, Liu P, Zhou L, Ehteshami M, Bassit L, Tao S, Domaoal RA, Sari O, Schutter C, Amiralaei S, Khalil A, Ollinger Russell O, McBrayer T, Whitaker T, Abou-Taleb N, Amblard F, Coats SJ, Schinazi RF.
Abstract : Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a β-d-2'-Cl,2'-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate 16 in its 5'-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent.
|
Antiviral activity against HCV genotype 1b Con1 expressing NS3 protease infected in human Huh-7 cells assessed as reduction in viral RNA replication after 72 hrs by luciferase reporter gene assay
|
Hepatitis C virus (isolate Con1)
|
284.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : The discovery of IDX21437: Design, synthesis and antiviral evaluation of 2'-α-chloro-2'-β-C-methyl branched uridine pronucleotides as potent liver-targeted HCV polymerase inhibitors.
Year : 2017
Volume : 27
Issue : 18
First Page : 4323
Last Page : 4330
Authors : Alexandre FR, Badaroux E, Bilello JP, Bot S, Bouisset T, Brandt G, Cappelle S, Chapron C, Chaves D, Convard T, Counor C, Da Costa D, Dukhan D, Gay M, Gosselin G, Griffon JF, Gupta K, Hernandez-Santiago B, La Colla M, Lioure MP, Milhau J, Paparin JL, Peyronnet J, Parsy C, Pierra Rouvière C, Rahali H, Rahali R, Salanson A, Seifer M, Serra I, Standring D, Surleraux D, Dousson CB.
Abstract : Herein we describe the discovery of IDX21437 35b, a novel RPd-aminoacid-based phosphoramidate prodrug of 2'-α-chloro-2'-β-C-methyluridine monophosphate. Its corresponding triphosphate 6 is a potent inhibitor of the HCV NS5B RNA-dependent RNA polymerase (RdRp). Despite showing very weak activity in the in vitro Huh-7 cell based HCV replicon assay, 35b demonstrated high levels of active triphosphate 6 in mouse liver and human hepatocytes. A biochemical study revealed that the metabolism of 35b was mainly attributed to carboxyesterase 1 (CES1), an enzyme which is underexpressed in HCV Huh-7-derived replicon cells. Furthermore, due to its metabolic activation, 35b was efficiently processed in liver cells compared to other cell types, including human cardiomyocytes. The selected RP diastereoisomeric configuration of 35b was assigned by X-ray structural determination. 35b is currently in Phase II clinical trials for the treatment of HCV infection.
|
Antiviral activity against HCV genotype 1b Con1 infected in human Huh-7 cells over-expressing CES1
|
Hepatitis C virus (isolate Con1)
|
552.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : The discovery of IDX21437: Design, synthesis and antiviral evaluation of 2'-α-chloro-2'-β-C-methyl branched uridine pronucleotides as potent liver-targeted HCV polymerase inhibitors.
Year : 2017
Volume : 27
Issue : 18
First Page : 4323
Last Page : 4330
Authors : Alexandre FR, Badaroux E, Bilello JP, Bot S, Bouisset T, Brandt G, Cappelle S, Chapron C, Chaves D, Convard T, Counor C, Da Costa D, Dukhan D, Gay M, Gosselin G, Griffon JF, Gupta K, Hernandez-Santiago B, La Colla M, Lioure MP, Milhau J, Paparin JL, Peyronnet J, Parsy C, Pierra Rouvière C, Rahali H, Rahali R, Salanson A, Seifer M, Serra I, Standring D, Surleraux D, Dousson CB.
Abstract : Herein we describe the discovery of IDX21437 35b, a novel RPd-aminoacid-based phosphoramidate prodrug of 2'-α-chloro-2'-β-C-methyluridine monophosphate. Its corresponding triphosphate 6 is a potent inhibitor of the HCV NS5B RNA-dependent RNA polymerase (RdRp). Despite showing very weak activity in the in vitro Huh-7 cell based HCV replicon assay, 35b demonstrated high levels of active triphosphate 6 in mouse liver and human hepatocytes. A biochemical study revealed that the metabolism of 35b was mainly attributed to carboxyesterase 1 (CES1), an enzyme which is underexpressed in HCV Huh-7-derived replicon cells. Furthermore, due to its metabolic activation, 35b was efficiently processed in liver cells compared to other cell types, including human cardiomyocytes. The selected RP diastereoisomeric configuration of 35b was assigned by X-ray structural determination. 35b is currently in Phase II clinical trials for the treatment of HCV infection.
|
Antiviral activity against HCV Jc1/JFH infected in human Huh7.5 cells assessed as reduction of pseudo-plaque formation after 72 hrs by immunoperoxidase monolayer assay
|
Hepatitis C virus
|
260.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel thioglycosyl analogs of glycosyltransferase substrates as antiviral compounds against classical swine fever virus and hepatitis C virus.
Year : 2017
Volume : 137
First Page : 247
Last Page : 262
Authors : Pastuch-Gawolek G, Chaubey B, Szewczyk B, Krol E.
Abstract : Hepatitis C virus (HCV) and classical swine fever virus (CSFV) are important pathogens for which new therapeutic approaches are in high demand. Herein, we report the synthesis of newly designed thioglycosyl analogs of glycosyltransferase substrates which were evaluated using cell-based assays for cytotoxicity and antiviral activity against both viruses. The antiviral activity of synthesized compounds against CSFV and HCV was confirmed using pseudo-plaque reduction assays where a significant arrest of viral growth was observed in the presence of selected compounds. We showed that compounds 13 and 14 exerted the most significant inhibitory effect on in vitro CSFV and HCV infections in the series. Glycoconjugates 13 and 14 not only inhibited both viral propagation with IC50 values in low micromolar range, but efficiently suppressed the production of viral proteins in a dose-dependent manner. In addition, studies using in vitro HCV infection and replication models have shown that both compounds are able to significantly reduce viral genomic replication. We demonstrated that compounds 13 and 14 showed a strong inhibition, up to 90% of replication which inscribe them in the promising alternative approach for the development of new anti-CSFV and anti-HCV drugs.
|
Antiviral activity against HCV infected in human Huh7-J17 cells assessed as inhibition of viral RNA replication after 72 hrs by bright-glo luciferase reporter assay
|
Hepatitis C virus
|
28.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel thioglycosyl analogs of glycosyltransferase substrates as antiviral compounds against classical swine fever virus and hepatitis C virus.
Year : 2017
Volume : 137
First Page : 247
Last Page : 262
Authors : Pastuch-Gawolek G, Chaubey B, Szewczyk B, Krol E.
Abstract : Hepatitis C virus (HCV) and classical swine fever virus (CSFV) are important pathogens for which new therapeutic approaches are in high demand. Herein, we report the synthesis of newly designed thioglycosyl analogs of glycosyltransferase substrates which were evaluated using cell-based assays for cytotoxicity and antiviral activity against both viruses. The antiviral activity of synthesized compounds against CSFV and HCV was confirmed using pseudo-plaque reduction assays where a significant arrest of viral growth was observed in the presence of selected compounds. We showed that compounds 13 and 14 exerted the most significant inhibitory effect on in vitro CSFV and HCV infections in the series. Glycoconjugates 13 and 14 not only inhibited both viral propagation with IC50 values in low micromolar range, but efficiently suppressed the production of viral proteins in a dose-dependent manner. In addition, studies using in vitro HCV infection and replication models have shown that both compounds are able to significantly reduce viral genomic replication. We demonstrated that compounds 13 and 14 showed a strong inhibition, up to 90% of replication which inscribe them in the promising alternative approach for the development of new anti-CSFV and anti-HCV drugs.
|
Antiviral activity against HCV genotype 1b infected in human HuH7 cells assessed as inhibition of viral RNA replication after 5 days by RT-PCR method
|
Hepatitis C virus subtype 1b
|
200.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and anti-HCV activity of a series of β-d-2'-deoxy-2'-dibromo nucleosides and their corresponding phosphoramidate prodrugs.
Year : 2017
Volume : 27
Issue : 23
First Page : 5296
Last Page : 5299
Authors : Chen Z, Cox BD, Garnier-Amblard EC, McBrayer TR, Coats SJ, Schinazi RF, Amblard F.
Abstract : Several β-d-2'-deoxy-2'-substituted nucleoside analogs have displayed potent and selective anti-HCV activities and some of them have reached human clinical trials. In that regard, we report herein the synthesis of a series of 2'-deoxy,2'-dibromo substituted U, C, G and A nucleosides 10a-d and their corresponding phosphoramidate prodrugs 13a-d. The synthesized nucleosides 10a-d and prodrugs 13a-d were evaluated for their inhibitory activity against HCV as well as cellular toxicity. The results showed that the most potent compound was prodrug 13a, which exhibited micromolar inhibitory activity (EC50 = 1.5 ± 0.8 µM) with no observed toxicity. In addition, molecular modeling and free energy perturbation calculations for the 5'-triphosphate formed from 13a and related 2'-modified nucleotides are discussed.
|
Inhibition of Hepatitis C virus genotype 1b NS5B RNA-dependent-RNA polymerase assessed as reduction in viral replication after 72 hrs by indirect immunofluorescence assay
|
Hepatitis C virus subtype 1b
|
64.26
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis, and structure-activity relationships of novel imidazo[4,5-c]pyridine derivatives as potent non-nucleoside inhibitors of hepatitis C virus NS5B.
Year : 2018
Volume : 26
Issue : 9
First Page : 2621
Last Page : 2631
Authors : Liu M, Xu Q, Guo S, Zuo R, Hong Y, Luo Y, Li Y, Gong P, Liu Y.
Abstract : The hepatitis C virus (HCV) NS5B polymerase is an attractive target for the development of novel and selective inhibitors of HCV replication. In this paper, the design, synthesis, and preliminary SAR studies of novel inhibitors of HCV NS5B polymerase based on the structure of tegobuvir have been described. The efforts to optimize the antiviral potency and reduce the treatment side effects with respect to genotype 1b resulted in the discovery of compound 3, which exhibited an EC50 of 1.163 nM and a CC50 >200 nM in a cell-based HCV replicon system assay. Additionally, testing for inhibition of the hERG channel showed a marked improvement over tegobuvir and the pharmacokinetic properties of compound 3 indicated that it was worthy of further investigation as a non-nucleoside inhibitor of HCV NS5B polymerase.
|
Antiviral activity against Hepatitis C virus JFH-1 infected in human HuH7 cells assessed as inhibition of viral RNA replication after 3 days by quantitative real-time RT-PCR analysis
|
Hepatitis C virus JFH-1
|
270.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of a novel β-D-2'-deoxy-2'-α-fluoro-2'-β-C-(fluoromethyl)uridine phosphoramidate prodrug for the treatment of hepatitis C virus infection.
Year : 2018
Volume : 143
First Page : 107
Last Page : 113
Authors : Li E, Wang Y, Yu W, Lv Z, Peng Y, Liu B, Li S, Ho W, Wang Q, Li H, Chang J.
Abstract : A novel β-D-2'-deoxy-2'-α-fluoro-2'-β-C-(fluoromethyl)uridine phosphoramidate prodrug (1) has been synthesized. This compound exhibits submicromolar-level antiviral activity in vitro against HCV genotypes 1b, 1a, 2a, and S282T replicons (EC50 = 0.18-1.13 μM) with low cytotoxicity (CC50 > 1000 μM). Administered orally, prodrug 1 is well tolerated at doses of up to 4 g/kg in mice, and produces a high level of the corresponding triphosphate in rat liver.
|
Antiviral activity against HCV JFH-1 harboring K78E/E2-G451R/NS3-M260K/NS5A-T462I mutant infected in human Huh7.5.1 cells after 2 days by renilla luciferase reporter gene assay
|
Hepatitis C virus
|
170.0
nM
|
|
Journal : J Med Chem
Title : Discovery, Optimization, and Target Identification of Novel Potent Broad-Spectrum Antiviral Inhibitors.
Year : 2019
Volume : 62
Issue : 8
First Page : 4056
Last Page : 4073
Authors : Yang Y, Cao L, Gao H, Wu Y, Wang Y, Fang F, Lan T, Lou Z, Rao Y.
Abstract : Viral infections are increasing and probably long-lasting global risks. In this study, a chemical library was exploited by phenotypic screening to discover new antiviral inhibitors. After optimizations from hit to lead, a novel potent small molecule (RYL-634) was identified, showing excellent broad-spectrum inhibition activity against various pathogenic viruses, including hepatitis C virus, dengue virus, Zika virus, chikungunya virus, enterovirus 71, human immunodeficiency virus, respiratory syncytial virus, and others. The mechanism of action and potential targets of RYL-634 were further explored by the combination of activity-based protein profiling and other techniques. Finally, human dihydroorotate dehydrogenase was validated as the major target of RYL-634. We did not observe any mutant resistance under our pressure selections with RYL-634, and it had a strong synergistic effect with some Food and Drug Administration-approved drugs. Hence, there is great potential for developing new broad-spectrum antivirals based on RYL-634.
|
Inhibition of RNA-dependent RNA polymerase in Zika virus infected in human NPC assessed as antiviral activity by DAPI-staining based assay
|
Zika virus
|
120.0
nM
|
|
Journal : J Med Chem
Title : Drugs for the Treatment of Zika Virus Infection.
Year : 2020
Volume : 63
Issue : 2
First Page : 470
Last Page : 489
Authors : Bernatchez JA, Tran LT, Li J, Luan Y, Siqueira-Neto JL, Li R.
Abstract : Zika virus is an emerging flavivirus that causes the neurodevelopmental congenital Zika syndrome and that has been linked to the neuroinflammatory Guillain-Barré syndrome. The absence of a vaccine or a clinically approved drug to treat the disease combined with the likelihood that another outbreak will occur in the future defines an unmet medical need. Several promising drug candidate molecules have been reported via repurposing studies, high-throughput compound library screening, and de novo design in the short span of a few years. Intense research activity in this area has occurred in response to the World Health Organization declaration of a Public Health Emergency of International Concern on February 1, 2016. In this Perspective, the authors review the emergence of Zika virus, the biology of its replication, targets for therapeutic intervention, target product profile, and current drug development initiatives.
|
Inhibition of HCV genotype 1b NS5B RNA dependent RNA polymerase
|
Hepatitis C virus subtype 1b
|
102.0
nM
|
|
Journal : MedChemComm
Title : Scaffold hybridization strategy towards potent hydroxamate-based inhibitors of <i>Flaviviridae</i> viruses and <i>Trypanosoma</i> species.
Year : 2019
Volume : 10
Issue : 6
First Page : 991
Last Page : 1006
Authors : Giannakopoulou E, Pardali V, Frakolaki E, Siozos V, Myrianthopoulos V, Mikros E, Taylor MC, Kelly JM, Vassilaki N, Zoidis G.
Abstract : Infections with <i>Flaviviridae</i> viruses, such as hepatitis C virus (HCV) and dengue virus (DENV) pose global health threats. Infected individuals are at risk of developing chronic liver failure or haemorrhagic fever respectively, often with a fatal outcome if left untreated. Diseases caused by tropical parasites of the <i>Trypanosoma</i> species, <i>T. brucei</i> and <i>T. cruzi</i>, constitute significant socioeconomic burden in sub-Saharan Africa and continental Latin America, yet drug development is under-funded. Anti-HCV chemotherapy is associated with severe side effects and high cost, while dengue has no clinically approved therapy and antiparasitic drugs are outdated and difficult to administer. Moreover, drug resistance is an emerging concern. Consequently, the need for new revolutionary chemotherapies is urgent. By utilizing a molecular framework combination approach, we combined two distinct chemical entities with proven antiviral and trypanocidal activity into a novel hybrid scaffold attached by an acetohydroxamic acid group (CH<sub>2</sub>CONHOH), aiming at derivatives with dual activity. The novel spiro-carbocyclic substituted hydantoin analogues were rationally designed, synthesized and evaluated for their potency against three HCV genotypes (1b, 3a, 4a), DENV and two <i>Trypanosoma</i> species (<i>T. brucei</i>, <i>T. cruzi</i>). They exhibited significant EC<sub>50</sub> values and remarkable selectivity indices. Several modifications were undertaken to further explore the structure activity relationships (SARs) and confirm the pivotal role of the acetohydroxamic acid metal binding group.
|
Antiviral activity against DENV2 New Guinea C/PUO-218 by qRT-PCR analysis
|
Dengue virus 2
|
400.0
nM
|
|
Journal : Eur J Med Chem
Title : Recent update on anti-dengue drug discovery.
Year : 2019
Volume : 176
First Page : 431
Last Page : 455
Authors : Dighe SN, Ekwudu O, Dua K, Chellappan DK, Katavic PL, Collet TA.
Abstract : Dengue is the most important arthropod-borne viral disease of humans, with more than half of the global population living in at-risk areas. Despite the negative impact on public health, there are no antiviral therapies available, and the only licensed vaccine, Dengvaxia<sup>®</sup>, has been contraindicated in children below nine years of age. In an effort to combat dengue, several small molecules have entered into human clinical trials. Here, we review anti-DENV molecules and their drug targets that have been published within the past five years (2014-2018). Further, we discuss their probable mechanisms of action and describe a role for classes of clinically approved drugs and also an unclassified class of anti-DENV agents. This review aims to enhance our understanding of novel agents and their cognate targets in furthering innovations in the use of small molecules for dengue drug therapies.
|
Inhibition of NS5B polymerase in HCV genotype 1b/3a chimeric replicon infected in human HuH7 replicon cells after 5 days by RT-PCR analysis
|
Hepatitis C virus
|
64.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a Series of 2'-α-Fluoro,2'-β-bromo-ribonucleosides and Their Phosphoramidate Prodrugs as Potent Pan-Genotypic Inhibitors of Hepatitis C Virus.
Year : 2019
Volume : 62
Issue : 4
First Page : 1859
Last Page : 1874
Authors : Mengshetti S, Zhou L, Sari O, De Schutter C, Zhang H, Cho JH, Tao S, Bassit LC, Verma K, Domaoal RA, Ehteshami M, Jiang Y, Ovadia R, Kasthuri M, Ollinger Russell O, McBrayer T, Whitaker T, Pattassery J, Pascual ML, Uher L, Lin BY, Lee S, Amblard F, Coats SJ, Schinazi RF.
Abstract : Hepatitis C virus (HCV) nucleoside inhibitors display pan-genotypic activity, a high barrier to the selection of resistant virus, and are some of the most potent direct-acting agents with durable sustained virologic response in humans. Herein, we report, the discovery of β-d-2'-Br,2'-F-uridine phosphoramidate diastereomers 27 and 28, as nontoxic pan-genotypic anti-HCV agents. Extensive profiling of these two phosphorous diastereomers was performed to select one for in-depth preclinical profiling. The 5'-triphosphate formed from these phosphoramidates selectively inhibited HCV NS5B polymerase with no inhibition of human polymerases and cellular mitochondrial RNA polymerase up to 100 μM. Both are nontoxic by a variety of measures and display good stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes. Ultimately, a preliminary oral pharmacokinetics study in male beagles showed that 28 is superior to 27 and is an attractive candidate for further studies to establish its potential value as a new clinical anti-HCV agent.
|
Inhibition of NS5B polymerase in HCV genotype 1b/4a chimeric replicon infected in human HuH7 replicon cells after 5 days by RT-PCR analysis
|
Hepatitis C virus
|
58.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a Series of 2'-α-Fluoro,2'-β-bromo-ribonucleosides and Their Phosphoramidate Prodrugs as Potent Pan-Genotypic Inhibitors of Hepatitis C Virus.
Year : 2019
Volume : 62
Issue : 4
First Page : 1859
Last Page : 1874
Authors : Mengshetti S, Zhou L, Sari O, De Schutter C, Zhang H, Cho JH, Tao S, Bassit LC, Verma K, Domaoal RA, Ehteshami M, Jiang Y, Ovadia R, Kasthuri M, Ollinger Russell O, McBrayer T, Whitaker T, Pattassery J, Pascual ML, Uher L, Lin BY, Lee S, Amblard F, Coats SJ, Schinazi RF.
Abstract : Hepatitis C virus (HCV) nucleoside inhibitors display pan-genotypic activity, a high barrier to the selection of resistant virus, and are some of the most potent direct-acting agents with durable sustained virologic response in humans. Herein, we report, the discovery of β-d-2'-Br,2'-F-uridine phosphoramidate diastereomers 27 and 28, as nontoxic pan-genotypic anti-HCV agents. Extensive profiling of these two phosphorous diastereomers was performed to select one for in-depth preclinical profiling. The 5'-triphosphate formed from these phosphoramidates selectively inhibited HCV NS5B polymerase with no inhibition of human polymerases and cellular mitochondrial RNA polymerase up to 100 μM. Both are nontoxic by a variety of measures and display good stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes. Ultimately, a preliminary oral pharmacokinetics study in male beagles showed that 28 is superior to 27 and is an attractive candidate for further studies to establish its potential value as a new clinical anti-HCV agent.
|
Inhibition of NS5B polymerase in HCV genotype 2a infected in human HuH7 replicon cells after 5 days by RT-PCR analysis
|
Hepatitis C virus subtype 2a
|
43.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a Series of 2'-α-Fluoro,2'-β-bromo-ribonucleosides and Their Phosphoramidate Prodrugs as Potent Pan-Genotypic Inhibitors of Hepatitis C Virus.
Year : 2019
Volume : 62
Issue : 4
First Page : 1859
Last Page : 1874
Authors : Mengshetti S, Zhou L, Sari O, De Schutter C, Zhang H, Cho JH, Tao S, Bassit LC, Verma K, Domaoal RA, Ehteshami M, Jiang Y, Ovadia R, Kasthuri M, Ollinger Russell O, McBrayer T, Whitaker T, Pattassery J, Pascual ML, Uher L, Lin BY, Lee S, Amblard F, Coats SJ, Schinazi RF.
Abstract : Hepatitis C virus (HCV) nucleoside inhibitors display pan-genotypic activity, a high barrier to the selection of resistant virus, and are some of the most potent direct-acting agents with durable sustained virologic response in humans. Herein, we report, the discovery of β-d-2'-Br,2'-F-uridine phosphoramidate diastereomers 27 and 28, as nontoxic pan-genotypic anti-HCV agents. Extensive profiling of these two phosphorous diastereomers was performed to select one for in-depth preclinical profiling. The 5'-triphosphate formed from these phosphoramidates selectively inhibited HCV NS5B polymerase with no inhibition of human polymerases and cellular mitochondrial RNA polymerase up to 100 μM. Both are nontoxic by a variety of measures and display good stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes. Ultimately, a preliminary oral pharmacokinetics study in male beagles showed that 28 is superior to 27 and is an attractive candidate for further studies to establish its potential value as a new clinical anti-HCV agent.
|
Inhibition of NS5B polymerase in HCV genotype 1a infected in human HuH7 replicon cells after 5 days by RT-PCR analysis
|
Hepatitis C virus subtype 1a
|
61.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a Series of 2'-α-Fluoro,2'-β-bromo-ribonucleosides and Their Phosphoramidate Prodrugs as Potent Pan-Genotypic Inhibitors of Hepatitis C Virus.
Year : 2019
Volume : 62
Issue : 4
First Page : 1859
Last Page : 1874
Authors : Mengshetti S, Zhou L, Sari O, De Schutter C, Zhang H, Cho JH, Tao S, Bassit LC, Verma K, Domaoal RA, Ehteshami M, Jiang Y, Ovadia R, Kasthuri M, Ollinger Russell O, McBrayer T, Whitaker T, Pattassery J, Pascual ML, Uher L, Lin BY, Lee S, Amblard F, Coats SJ, Schinazi RF.
Abstract : Hepatitis C virus (HCV) nucleoside inhibitors display pan-genotypic activity, a high barrier to the selection of resistant virus, and are some of the most potent direct-acting agents with durable sustained virologic response in humans. Herein, we report, the discovery of β-d-2'-Br,2'-F-uridine phosphoramidate diastereomers 27 and 28, as nontoxic pan-genotypic anti-HCV agents. Extensive profiling of these two phosphorous diastereomers was performed to select one for in-depth preclinical profiling. The 5'-triphosphate formed from these phosphoramidates selectively inhibited HCV NS5B polymerase with no inhibition of human polymerases and cellular mitochondrial RNA polymerase up to 100 μM. Both are nontoxic by a variety of measures and display good stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes. Ultimately, a preliminary oral pharmacokinetics study in male beagles showed that 28 is superior to 27 and is an attractive candidate for further studies to establish its potential value as a new clinical anti-HCV agent.
|
Inhibition of NS5B polymerase in wild type HCV genotype 1b infected in human Huh7 replicon cells after 5 days by RT-PCR assay
|
Hepatitis C virus subtype 1b
|
34.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a Series of 2'-α-Fluoro,2'-β-bromo-ribonucleosides and Their Phosphoramidate Prodrugs as Potent Pan-Genotypic Inhibitors of Hepatitis C Virus.
Year : 2019
Volume : 62
Issue : 4
First Page : 1859
Last Page : 1874
Authors : Mengshetti S, Zhou L, Sari O, De Schutter C, Zhang H, Cho JH, Tao S, Bassit LC, Verma K, Domaoal RA, Ehteshami M, Jiang Y, Ovadia R, Kasthuri M, Ollinger Russell O, McBrayer T, Whitaker T, Pattassery J, Pascual ML, Uher L, Lin BY, Lee S, Amblard F, Coats SJ, Schinazi RF.
Abstract : Hepatitis C virus (HCV) nucleoside inhibitors display pan-genotypic activity, a high barrier to the selection of resistant virus, and are some of the most potent direct-acting agents with durable sustained virologic response in humans. Herein, we report, the discovery of β-d-2'-Br,2'-F-uridine phosphoramidate diastereomers 27 and 28, as nontoxic pan-genotypic anti-HCV agents. Extensive profiling of these two phosphorous diastereomers was performed to select one for in-depth preclinical profiling. The 5'-triphosphate formed from these phosphoramidates selectively inhibited HCV NS5B polymerase with no inhibition of human polymerases and cellular mitochondrial RNA polymerase up to 100 μM. Both are nontoxic by a variety of measures and display good stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes. Ultimately, a preliminary oral pharmacokinetics study in male beagles showed that 28 is superior to 27 and is an attractive candidate for further studies to establish its potential value as a new clinical anti-HCV agent.
|
Inhibition of NS5B polymerase in HCV genotype 1b/5a chimeric replicon infected in human HuH7 replicon cells after 5 days by RT-PCR analysis
|
Hepatitis C virus
|
44.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a Series of 2'-α-Fluoro,2'-β-bromo-ribonucleosides and Their Phosphoramidate Prodrugs as Potent Pan-Genotypic Inhibitors of Hepatitis C Virus.
Year : 2019
Volume : 62
Issue : 4
First Page : 1859
Last Page : 1874
Authors : Mengshetti S, Zhou L, Sari O, De Schutter C, Zhang H, Cho JH, Tao S, Bassit LC, Verma K, Domaoal RA, Ehteshami M, Jiang Y, Ovadia R, Kasthuri M, Ollinger Russell O, McBrayer T, Whitaker T, Pattassery J, Pascual ML, Uher L, Lin BY, Lee S, Amblard F, Coats SJ, Schinazi RF.
Abstract : Hepatitis C virus (HCV) nucleoside inhibitors display pan-genotypic activity, a high barrier to the selection of resistant virus, and are some of the most potent direct-acting agents with durable sustained virologic response in humans. Herein, we report, the discovery of β-d-2'-Br,2'-F-uridine phosphoramidate diastereomers 27 and 28, as nontoxic pan-genotypic anti-HCV agents. Extensive profiling of these two phosphorous diastereomers was performed to select one for in-depth preclinical profiling. The 5'-triphosphate formed from these phosphoramidates selectively inhibited HCV NS5B polymerase with no inhibition of human polymerases and cellular mitochondrial RNA polymerase up to 100 μM. Both are nontoxic by a variety of measures and display good stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes. Ultimately, a preliminary oral pharmacokinetics study in male beagles showed that 28 is superior to 27 and is an attractive candidate for further studies to establish its potential value as a new clinical anti-HCV agent.
|
Inhibition of NS5B polymerase S282T mutant in HCV genotype 1b infected in human Huh7 replicon cells after 5 days by RT-PCR assay
|
Hepatitis C virus subtype 1b
|
300.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a Series of 2'-α-Fluoro,2'-β-bromo-ribonucleosides and Their Phosphoramidate Prodrugs as Potent Pan-Genotypic Inhibitors of Hepatitis C Virus.
Year : 2019
Volume : 62
Issue : 4
First Page : 1859
Last Page : 1874
Authors : Mengshetti S, Zhou L, Sari O, De Schutter C, Zhang H, Cho JH, Tao S, Bassit LC, Verma K, Domaoal RA, Ehteshami M, Jiang Y, Ovadia R, Kasthuri M, Ollinger Russell O, McBrayer T, Whitaker T, Pattassery J, Pascual ML, Uher L, Lin BY, Lee S, Amblard F, Coats SJ, Schinazi RF.
Abstract : Hepatitis C virus (HCV) nucleoside inhibitors display pan-genotypic activity, a high barrier to the selection of resistant virus, and are some of the most potent direct-acting agents with durable sustained virologic response in humans. Herein, we report, the discovery of β-d-2'-Br,2'-F-uridine phosphoramidate diastereomers 27 and 28, as nontoxic pan-genotypic anti-HCV agents. Extensive profiling of these two phosphorous diastereomers was performed to select one for in-depth preclinical profiling. The 5'-triphosphate formed from these phosphoramidates selectively inhibited HCV NS5B polymerase with no inhibition of human polymerases and cellular mitochondrial RNA polymerase up to 100 μM. Both are nontoxic by a variety of measures and display good stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes. Ultimately, a preliminary oral pharmacokinetics study in male beagles showed that 28 is superior to 27 and is an attractive candidate for further studies to establish its potential value as a new clinical anti-HCV agent.
|
Mitochondrial toxicity in human HepG2 cells assessed as inhibition of cytochrome c oxidase subunit 2 DNA level at 50 uM followed by medium plus drugs replenishment every 3 to 4 days for 14 days relative to control
|
Homo sapiens
|
44.0
%
|
|
Journal : J Med Chem
Title : Discovery of a Series of 2'-α-Fluoro,2'-β-bromo-ribonucleosides and Their Phosphoramidate Prodrugs as Potent Pan-Genotypic Inhibitors of Hepatitis C Virus.
Year : 2019
Volume : 62
Issue : 4
First Page : 1859
Last Page : 1874
Authors : Mengshetti S, Zhou L, Sari O, De Schutter C, Zhang H, Cho JH, Tao S, Bassit LC, Verma K, Domaoal RA, Ehteshami M, Jiang Y, Ovadia R, Kasthuri M, Ollinger Russell O, McBrayer T, Whitaker T, Pattassery J, Pascual ML, Uher L, Lin BY, Lee S, Amblard F, Coats SJ, Schinazi RF.
Abstract : Hepatitis C virus (HCV) nucleoside inhibitors display pan-genotypic activity, a high barrier to the selection of resistant virus, and are some of the most potent direct-acting agents with durable sustained virologic response in humans. Herein, we report, the discovery of β-d-2'-Br,2'-F-uridine phosphoramidate diastereomers 27 and 28, as nontoxic pan-genotypic anti-HCV agents. Extensive profiling of these two phosphorous diastereomers was performed to select one for in-depth preclinical profiling. The 5'-triphosphate formed from these phosphoramidates selectively inhibited HCV NS5B polymerase with no inhibition of human polymerases and cellular mitochondrial RNA polymerase up to 100 μM. Both are nontoxic by a variety of measures and display good stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes. Ultimately, a preliminary oral pharmacokinetics study in male beagles showed that 28 is superior to 27 and is an attractive candidate for further studies to establish its potential value as a new clinical anti-HCV agent.
|
Mitochondrial toxicity in human HepG2 cells assessed as inhibition of nuclear ribosomal-DNA level at 50 uM followed by medium plus drugs replenishment every 3 to 4 days for 14 days relative to control
|
Homo sapiens
|
58.0
%
|
|
Journal : J Med Chem
Title : Discovery of a Series of 2'-α-Fluoro,2'-β-bromo-ribonucleosides and Their Phosphoramidate Prodrugs as Potent Pan-Genotypic Inhibitors of Hepatitis C Virus.
Year : 2019
Volume : 62
Issue : 4
First Page : 1859
Last Page : 1874
Authors : Mengshetti S, Zhou L, Sari O, De Schutter C, Zhang H, Cho JH, Tao S, Bassit LC, Verma K, Domaoal RA, Ehteshami M, Jiang Y, Ovadia R, Kasthuri M, Ollinger Russell O, McBrayer T, Whitaker T, Pattassery J, Pascual ML, Uher L, Lin BY, Lee S, Amblard F, Coats SJ, Schinazi RF.
Abstract : Hepatitis C virus (HCV) nucleoside inhibitors display pan-genotypic activity, a high barrier to the selection of resistant virus, and are some of the most potent direct-acting agents with durable sustained virologic response in humans. Herein, we report, the discovery of β-d-2'-Br,2'-F-uridine phosphoramidate diastereomers 27 and 28, as nontoxic pan-genotypic anti-HCV agents. Extensive profiling of these two phosphorous diastereomers was performed to select one for in-depth preclinical profiling. The 5'-triphosphate formed from these phosphoramidates selectively inhibited HCV NS5B polymerase with no inhibition of human polymerases and cellular mitochondrial RNA polymerase up to 100 μM. Both are nontoxic by a variety of measures and display good stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes. Ultimately, a preliminary oral pharmacokinetics study in male beagles showed that 28 is superior to 27 and is an attractive candidate for further studies to establish its potential value as a new clinical anti-HCV agent.
|
Mitochondrial toxicity in human HepG2 cells assessed as inhibition of cytochrome c oxidase subunit 2 DNA level at 12.5 uM followed by medium plus drugs replenishment every 3 to 4 days for 14 days relative to control
|
Homo sapiens
|
6.7
%
|
|
Journal : J Med Chem
Title : Discovery of a Series of 2'-α-Fluoro,2'-β-bromo-ribonucleosides and Their Phosphoramidate Prodrugs as Potent Pan-Genotypic Inhibitors of Hepatitis C Virus.
Year : 2019
Volume : 62
Issue : 4
First Page : 1859
Last Page : 1874
Authors : Mengshetti S, Zhou L, Sari O, De Schutter C, Zhang H, Cho JH, Tao S, Bassit LC, Verma K, Domaoal RA, Ehteshami M, Jiang Y, Ovadia R, Kasthuri M, Ollinger Russell O, McBrayer T, Whitaker T, Pattassery J, Pascual ML, Uher L, Lin BY, Lee S, Amblard F, Coats SJ, Schinazi RF.
Abstract : Hepatitis C virus (HCV) nucleoside inhibitors display pan-genotypic activity, a high barrier to the selection of resistant virus, and are some of the most potent direct-acting agents with durable sustained virologic response in humans. Herein, we report, the discovery of β-d-2'-Br,2'-F-uridine phosphoramidate diastereomers 27 and 28, as nontoxic pan-genotypic anti-HCV agents. Extensive profiling of these two phosphorous diastereomers was performed to select one for in-depth preclinical profiling. The 5'-triphosphate formed from these phosphoramidates selectively inhibited HCV NS5B polymerase with no inhibition of human polymerases and cellular mitochondrial RNA polymerase up to 100 μM. Both are nontoxic by a variety of measures and display good stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes. Ultimately, a preliminary oral pharmacokinetics study in male beagles showed that 28 is superior to 27 and is an attractive candidate for further studies to establish its potential value as a new clinical anti-HCV agent.
|
Mitochondrial toxicity in human HepG2 cells assessed as inhibition of nuclear ribosomal-DNA level at 12.5 uM followed by medium plus drugs replenishment every 3 to 4 days for 14 days relative to control
|
Homo sapiens
|
3.1
%
|
|
Journal : J Med Chem
Title : Discovery of a Series of 2'-α-Fluoro,2'-β-bromo-ribonucleosides and Their Phosphoramidate Prodrugs as Potent Pan-Genotypic Inhibitors of Hepatitis C Virus.
Year : 2019
Volume : 62
Issue : 4
First Page : 1859
Last Page : 1874
Authors : Mengshetti S, Zhou L, Sari O, De Schutter C, Zhang H, Cho JH, Tao S, Bassit LC, Verma K, Domaoal RA, Ehteshami M, Jiang Y, Ovadia R, Kasthuri M, Ollinger Russell O, McBrayer T, Whitaker T, Pattassery J, Pascual ML, Uher L, Lin BY, Lee S, Amblard F, Coats SJ, Schinazi RF.
Abstract : Hepatitis C virus (HCV) nucleoside inhibitors display pan-genotypic activity, a high barrier to the selection of resistant virus, and are some of the most potent direct-acting agents with durable sustained virologic response in humans. Herein, we report, the discovery of β-d-2'-Br,2'-F-uridine phosphoramidate diastereomers 27 and 28, as nontoxic pan-genotypic anti-HCV agents. Extensive profiling of these two phosphorous diastereomers was performed to select one for in-depth preclinical profiling. The 5'-triphosphate formed from these phosphoramidates selectively inhibited HCV NS5B polymerase with no inhibition of human polymerases and cellular mitochondrial RNA polymerase up to 100 μM. Both are nontoxic by a variety of measures and display good stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes. Ultimately, a preliminary oral pharmacokinetics study in male beagles showed that 28 is superior to 27 and is an attractive candidate for further studies to establish its potential value as a new clinical anti-HCV agent.
|
Antiviral activity against HCV genotype 1b subgenomic replicon infected in human HuH7 clone B cells assessed as inhibition of viral RNA replication after 5 days by RT-PCR method
|
Hepatitis C virus
|
50.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and anti-HCV activity of β-d-2'-deoxy-2'-α-chloro-2'-β-fluoro and β-d-2'-deoxy-2'-α-bromo-2'-β-fluoro nucleosides and their phosphoramidate prodrugs.
Year : 2019
Volume : 27
Issue : 4
First Page : 664
Last Page : 676
Authors : Ovadia R, Khalil A, Li H, De Schutter C, Mengshetti S, Zhou S, Bassit L, Coats SJ, Amblard F, Schinazi RF.
Abstract : We report herein the synthesis and evaluation of a series of β-d-2'-deoxy-2'-α-chloro-2'-β-fluoro and β-d-2'-deoxy-2'-α-bromo-2'-β-fluoro nucleosides along with their corresponding phosphoramidate prodrugs. Key intermediates, lactols 11 and 12, were obtained by a diastereoselective fluorination of protected 2-deoxy-2-chloro/bromo-ribonolactones 7 and 8. All synthesized nucleosides and prodrugs were evaluated with a hepatitis C virus (HCV) subgenomic replicon system.
|
Antiviral activity against HCV genotype 1b replicon infected in human HuH7 cells after 72 hrs by bright-glo luciferase reporter gene assay
|
Hepatitis C virus
|
180.0
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery of pyrimidine nucleoside dual prodrugs and pyrazine nucleosides as novel anti-HCV agents.
Year : 2019
Volume : 27
Issue : 5
First Page : 748
Last Page : 759
Authors : Guo S, Xu M, Guo Q, Zhu F, Jiang X, Xie Y, Shen J.
Abstract : To explore the application potential of dual prodrug strategies in the development of anti-HCV agents, a variety of sofosbuvir derivatives with modifications at the C4 or N3 position of the uracil moiety were designed and synthesized. Some compounds exhibited potent anti-HCV activities, such as 4e and 8a-8c with similar EC50 values (0.20-0.22 μM) comparative to that of sofosbuvir (EC50 = 0.18 μM) in a genotype 1b based replicon Huh-7 cell line. Moreover, 8b displayed a good human plasma stability profile, and was easily metabolized in human liver microsomes expectantly. On the other hand, aiming to discover novel anti-HCV nucleosides, pyrazin-2(1H)-one nucleosides and their phosphoramidate prodrugs were investigated. Several active compounds were discovered, such as 25e (EC50 = 7.3 μM) and S-29b (EC50 = 19.5 μM). This kind of nucleosides were interesting and would open a new avenue for the development of antiviral agents.
|
Antiviral activity against HCV genotype 1b replicon infected in human HuH7 cells at 20 uM after 72 hrs by bright-glo luciferase reporter gene assay relative to control
|
Hepatitis C virus
|
99.9
%
|
|
Journal : Bioorg Med Chem
Title : Discovery of pyrimidine nucleoside dual prodrugs and pyrazine nucleosides as novel anti-HCV agents.
Year : 2019
Volume : 27
Issue : 5
First Page : 748
Last Page : 759
Authors : Guo S, Xu M, Guo Q, Zhu F, Jiang X, Xie Y, Shen J.
Abstract : To explore the application potential of dual prodrug strategies in the development of anti-HCV agents, a variety of sofosbuvir derivatives with modifications at the C4 or N3 position of the uracil moiety were designed and synthesized. Some compounds exhibited potent anti-HCV activities, such as 4e and 8a-8c with similar EC50 values (0.20-0.22 μM) comparative to that of sofosbuvir (EC50 = 0.18 μM) in a genotype 1b based replicon Huh-7 cell line. Moreover, 8b displayed a good human plasma stability profile, and was easily metabolized in human liver microsomes expectantly. On the other hand, aiming to discover novel anti-HCV nucleosides, pyrazin-2(1H)-one nucleosides and their phosphoramidate prodrugs were investigated. Several active compounds were discovered, such as 25e (EC50 = 7.3 μM) and S-29b (EC50 = 19.5 μM). This kind of nucleosides were interesting and would open a new avenue for the development of antiviral agents.
|
Inhibition of HCV NS3/4a protease
|
Hepatitis C virus
|
61.0
%
|
|
Journal : Eur J Med Chem
Title : Hepatitis C - New drugs and treatment prospects.
Year : 2019
Volume : 165
First Page : 225
Last Page : 249
Authors : Zając M, Muszalska I, Sobczak A, Dadej A, Tomczak S, Jelińska A.
Abstract : Hepatitis C virus (HCV) affects approx. 3% of the world's population and accounts for ca 300 000 deaths per year. 80% of individuals with HCV develop chronic symptoms which, when untreated, may cause cirrhosis (27%) or hepatocellular carcinoma (25%). The hepatitis C virus is a (+)ssRNA enveloped virus of the family Flaviviridae. Seven major HCV genotypes and their subtypes (a, b) have been identified. In the 1990s, interferons alpha-2 were used in the treatment of HCV and in the next decade HCV therapy was based on pegylated interferon alpha-2 in combination with ribavirin. Since 2011, interferons alpha, DNA and RNA polymerase inhibitors, NS3/4A RNA protease inhibitors, NS5 RNA serine protease inhibitors, NS5B RNA polymerase inhibitors have been approved for clinical use. Monotherapy is avoided in medication due to rapidly developing viral resistance. A total of 113 papers were included comprising original publications and reviews. The paper reviews the molecular targets and chemical structures of drugs used in HCV treatment. Indications and contraindications for anti-HCV drugs are also discussed together with application regimens.
|
Antiviral activity against HCV genotype 1a H77 infected in human HuH7 replicon cells assessed as inhibition of viral replication after 3 days by luciferase reporter gene assay
|
Hepatitis C virus
|
155.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of 2'-dihalo ribonucleotide prodrugs with activity against hepatitis C virus.
Year : 2020
Volume : 28
Issue : 1
First Page : 115208
Last Page : 115208
Authors : Chris Krueger A, Chen HJ, Randolph JT, Brown BS, Halvorsen GT, Heyman HR, Li T, Marvin CC, Shanley JP, Voight EA, Bow DAJ, Van Handel C, Peterkin V, Carr RA, Stolarik D, Dekhtyar T, Irvin ML, Krishnan P, Henry RF, Wagner R, DeGoey DA.
Abstract : Hepatitis C virus (HCV) nucleoside inhibitors have been a key focus of nearly 2 decades of HCV drug research due to a high barrier to drug resistance and pan-genotypic activity profile provided by molecules in this drug class. Our investigations focused on several potent 2'-halogenated uridine-based HCV polymerase inhibitors, resulting in the discovery of novel 2'-deoxy-2'-dihalo-uridine analogs that are potent inhibitors in replicon assays for all genotypes. Further studies to improve in vivo performance of these nucleoside inhibitors identified aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs 18a and 18c, which provide high levels of the active triphosphate in dog liver. AIBEE prodrug 18c was compared with sofosbuvir (1) by co-dosing both compounds by oral administration in dog (5 mg/kg each) and measuring liver concentrations of the active triphosphate metabolite at both 4 and 24 h post dosing. In this study, 18c provided liver triphosphate concentrations that were 6-fold higher than sofosbuvir (1) at both biopsy time points, suggesting that 18c could be a highly effective agent for treating HCV infected patients in the clinic.
|
Antiviral activity against HCV genotype 1b Con1 infected in human HuH7 replicon cells assessed as inhibition of viral replication after 3 days by luciferase reporter gene assay
|
Hepatitis C virus
|
188.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of 2'-dihalo ribonucleotide prodrugs with activity against hepatitis C virus.
Year : 2020
Volume : 28
Issue : 1
First Page : 115208
Last Page : 115208
Authors : Chris Krueger A, Chen HJ, Randolph JT, Brown BS, Halvorsen GT, Heyman HR, Li T, Marvin CC, Shanley JP, Voight EA, Bow DAJ, Van Handel C, Peterkin V, Carr RA, Stolarik D, Dekhtyar T, Irvin ML, Krishnan P, Henry RF, Wagner R, DeGoey DA.
Abstract : Hepatitis C virus (HCV) nucleoside inhibitors have been a key focus of nearly 2 decades of HCV drug research due to a high barrier to drug resistance and pan-genotypic activity profile provided by molecules in this drug class. Our investigations focused on several potent 2'-halogenated uridine-based HCV polymerase inhibitors, resulting in the discovery of novel 2'-deoxy-2'-dihalo-uridine analogs that are potent inhibitors in replicon assays for all genotypes. Further studies to improve in vivo performance of these nucleoside inhibitors identified aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs 18a and 18c, which provide high levels of the active triphosphate in dog liver. AIBEE prodrug 18c was compared with sofosbuvir (1) by co-dosing both compounds by oral administration in dog (5 mg/kg each) and measuring liver concentrations of the active triphosphate metabolite at both 4 and 24 h post dosing. In this study, 18c provided liver triphosphate concentrations that were 6-fold higher than sofosbuvir (1) at both biopsy time points, suggesting that 18c could be a highly effective agent for treating HCV infected patients in the clinic.
|
Antiviral activity against HCV genotype 1b Con1 expressing wild type NS5B infected in human HuH7 replicon cells assessed as inhibition of viral replication after 4 days by luciferase reporter gene based assay
|
Hepatitis C virus
|
62.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of 2'-dihalo ribonucleotide prodrugs with activity against hepatitis C virus.
Year : 2020
Volume : 28
Issue : 1
First Page : 115208
Last Page : 115208
Authors : Chris Krueger A, Chen HJ, Randolph JT, Brown BS, Halvorsen GT, Heyman HR, Li T, Marvin CC, Shanley JP, Voight EA, Bow DAJ, Van Handel C, Peterkin V, Carr RA, Stolarik D, Dekhtyar T, Irvin ML, Krishnan P, Henry RF, Wagner R, DeGoey DA.
Abstract : Hepatitis C virus (HCV) nucleoside inhibitors have been a key focus of nearly 2 decades of HCV drug research due to a high barrier to drug resistance and pan-genotypic activity profile provided by molecules in this drug class. Our investigations focused on several potent 2'-halogenated uridine-based HCV polymerase inhibitors, resulting in the discovery of novel 2'-deoxy-2'-dihalo-uridine analogs that are potent inhibitors in replicon assays for all genotypes. Further studies to improve in vivo performance of these nucleoside inhibitors identified aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs 18a and 18c, which provide high levels of the active triphosphate in dog liver. AIBEE prodrug 18c was compared with sofosbuvir (1) by co-dosing both compounds by oral administration in dog (5 mg/kg each) and measuring liver concentrations of the active triphosphate metabolite at both 4 and 24 h post dosing. In this study, 18c provided liver triphosphate concentrations that were 6-fold higher than sofosbuvir (1) at both biopsy time points, suggesting that 18c could be a highly effective agent for treating HCV infected patients in the clinic.
|
Antiviral activity against HCV genotype 1b Con1 expressing NS5B S282T mutant infected in human HuH7 replicon cells assessed as inhibition of viral replication after 4 days by luciferase reporter gene based assay
|
Hepatitis C virus
|
637.6
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of 2'-dihalo ribonucleotide prodrugs with activity against hepatitis C virus.
Year : 2020
Volume : 28
Issue : 1
First Page : 115208
Last Page : 115208
Authors : Chris Krueger A, Chen HJ, Randolph JT, Brown BS, Halvorsen GT, Heyman HR, Li T, Marvin CC, Shanley JP, Voight EA, Bow DAJ, Van Handel C, Peterkin V, Carr RA, Stolarik D, Dekhtyar T, Irvin ML, Krishnan P, Henry RF, Wagner R, DeGoey DA.
Abstract : Hepatitis C virus (HCV) nucleoside inhibitors have been a key focus of nearly 2 decades of HCV drug research due to a high barrier to drug resistance and pan-genotypic activity profile provided by molecules in this drug class. Our investigations focused on several potent 2'-halogenated uridine-based HCV polymerase inhibitors, resulting in the discovery of novel 2'-deoxy-2'-dihalo-uridine analogs that are potent inhibitors in replicon assays for all genotypes. Further studies to improve in vivo performance of these nucleoside inhibitors identified aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs 18a and 18c, which provide high levels of the active triphosphate in dog liver. AIBEE prodrug 18c was compared with sofosbuvir (1) by co-dosing both compounds by oral administration in dog (5 mg/kg each) and measuring liver concentrations of the active triphosphate metabolite at both 4 and 24 h post dosing. In this study, 18c provided liver triphosphate concentrations that were 6-fold higher than sofosbuvir (1) at both biopsy time points, suggesting that 18c could be a highly effective agent for treating HCV infected patients in the clinic.
|
Antiviral activity against HCV genotype 2a expressing wild type NS5B infected in human HuH7 replicon cells assessed as inhibition of viral replication after 4 days by luciferase reporter gene based assay
|
Hepatitis C virus
|
681.3
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of 2'-dihalo ribonucleotide prodrugs with activity against hepatitis C virus.
Year : 2020
Volume : 28
Issue : 1
First Page : 115208
Last Page : 115208
Authors : Chris Krueger A, Chen HJ, Randolph JT, Brown BS, Halvorsen GT, Heyman HR, Li T, Marvin CC, Shanley JP, Voight EA, Bow DAJ, Van Handel C, Peterkin V, Carr RA, Stolarik D, Dekhtyar T, Irvin ML, Krishnan P, Henry RF, Wagner R, DeGoey DA.
Abstract : Hepatitis C virus (HCV) nucleoside inhibitors have been a key focus of nearly 2 decades of HCV drug research due to a high barrier to drug resistance and pan-genotypic activity profile provided by molecules in this drug class. Our investigations focused on several potent 2'-halogenated uridine-based HCV polymerase inhibitors, resulting in the discovery of novel 2'-deoxy-2'-dihalo-uridine analogs that are potent inhibitors in replicon assays for all genotypes. Further studies to improve in vivo performance of these nucleoside inhibitors identified aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs 18a and 18c, which provide high levels of the active triphosphate in dog liver. AIBEE prodrug 18c was compared with sofosbuvir (1) by co-dosing both compounds by oral administration in dog (5 mg/kg each) and measuring liver concentrations of the active triphosphate metabolite at both 4 and 24 h post dosing. In this study, 18c provided liver triphosphate concentrations that were 6-fold higher than sofosbuvir (1) at both biopsy time points, suggesting that 18c could be a highly effective agent for treating HCV infected patients in the clinic.
|
Antiviral activity against HCV genotype 3a expressing wild type NS5B infected in human HuH7 replicon cells assessed as inhibition of viral replication after 4 days by luciferase reporter gene based assay
|
Hepatitis C virus
|
75.1
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of 2'-dihalo ribonucleotide prodrugs with activity against hepatitis C virus.
Year : 2020
Volume : 28
Issue : 1
First Page : 115208
Last Page : 115208
Authors : Chris Krueger A, Chen HJ, Randolph JT, Brown BS, Halvorsen GT, Heyman HR, Li T, Marvin CC, Shanley JP, Voight EA, Bow DAJ, Van Handel C, Peterkin V, Carr RA, Stolarik D, Dekhtyar T, Irvin ML, Krishnan P, Henry RF, Wagner R, DeGoey DA.
Abstract : Hepatitis C virus (HCV) nucleoside inhibitors have been a key focus of nearly 2 decades of HCV drug research due to a high barrier to drug resistance and pan-genotypic activity profile provided by molecules in this drug class. Our investigations focused on several potent 2'-halogenated uridine-based HCV polymerase inhibitors, resulting in the discovery of novel 2'-deoxy-2'-dihalo-uridine analogs that are potent inhibitors in replicon assays for all genotypes. Further studies to improve in vivo performance of these nucleoside inhibitors identified aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs 18a and 18c, which provide high levels of the active triphosphate in dog liver. AIBEE prodrug 18c was compared with sofosbuvir (1) by co-dosing both compounds by oral administration in dog (5 mg/kg each) and measuring liver concentrations of the active triphosphate metabolite at both 4 and 24 h post dosing. In this study, 18c provided liver triphosphate concentrations that were 6-fold higher than sofosbuvir (1) at both biopsy time points, suggesting that 18c could be a highly effective agent for treating HCV infected patients in the clinic.
|
Antiviral activity against HCV genotype 3a expressing NS5B S282T mutant infected in human HuH7 replicon cells assessed as inhibition of viral replication after 4 days by luciferase reporter gene based assay
|
Hepatitis C virus
|
330.1
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of 2'-dihalo ribonucleotide prodrugs with activity against hepatitis C virus.
Year : 2020
Volume : 28
Issue : 1
First Page : 115208
Last Page : 115208
Authors : Chris Krueger A, Chen HJ, Randolph JT, Brown BS, Halvorsen GT, Heyman HR, Li T, Marvin CC, Shanley JP, Voight EA, Bow DAJ, Van Handel C, Peterkin V, Carr RA, Stolarik D, Dekhtyar T, Irvin ML, Krishnan P, Henry RF, Wagner R, DeGoey DA.
Abstract : Hepatitis C virus (HCV) nucleoside inhibitors have been a key focus of nearly 2 decades of HCV drug research due to a high barrier to drug resistance and pan-genotypic activity profile provided by molecules in this drug class. Our investigations focused on several potent 2'-halogenated uridine-based HCV polymerase inhibitors, resulting in the discovery of novel 2'-deoxy-2'-dihalo-uridine analogs that are potent inhibitors in replicon assays for all genotypes. Further studies to improve in vivo performance of these nucleoside inhibitors identified aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs 18a and 18c, which provide high levels of the active triphosphate in dog liver. AIBEE prodrug 18c was compared with sofosbuvir (1) by co-dosing both compounds by oral administration in dog (5 mg/kg each) and measuring liver concentrations of the active triphosphate metabolite at both 4 and 24 h post dosing. In this study, 18c provided liver triphosphate concentrations that were 6-fold higher than sofosbuvir (1) at both biopsy time points, suggesting that 18c could be a highly effective agent for treating HCV infected patients in the clinic.
|
Antiviral activity against HCV genotype 4a expressing wild type NS5B infected in human HuH7 replicon cells assessed as inhibition of viral replication after 4 days by luciferase reporter gene based assay
|
Hepatitis C virus
|
78.5
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of 2'-dihalo ribonucleotide prodrugs with activity against hepatitis C virus.
Year : 2020
Volume : 28
Issue : 1
First Page : 115208
Last Page : 115208
Authors : Chris Krueger A, Chen HJ, Randolph JT, Brown BS, Halvorsen GT, Heyman HR, Li T, Marvin CC, Shanley JP, Voight EA, Bow DAJ, Van Handel C, Peterkin V, Carr RA, Stolarik D, Dekhtyar T, Irvin ML, Krishnan P, Henry RF, Wagner R, DeGoey DA.
Abstract : Hepatitis C virus (HCV) nucleoside inhibitors have been a key focus of nearly 2 decades of HCV drug research due to a high barrier to drug resistance and pan-genotypic activity profile provided by molecules in this drug class. Our investigations focused on several potent 2'-halogenated uridine-based HCV polymerase inhibitors, resulting in the discovery of novel 2'-deoxy-2'-dihalo-uridine analogs that are potent inhibitors in replicon assays for all genotypes. Further studies to improve in vivo performance of these nucleoside inhibitors identified aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs 18a and 18c, which provide high levels of the active triphosphate in dog liver. AIBEE prodrug 18c was compared with sofosbuvir (1) by co-dosing both compounds by oral administration in dog (5 mg/kg each) and measuring liver concentrations of the active triphosphate metabolite at both 4 and 24 h post dosing. In this study, 18c provided liver triphosphate concentrations that were 6-fold higher than sofosbuvir (1) at both biopsy time points, suggesting that 18c could be a highly effective agent for treating HCV infected patients in the clinic.
|
Antiviral activity against HCV genotype 6a expressing wild type NS5B infected in human HuH7 replicon cells assessed as inhibition of viral replication after 4 days by luciferase reporter gene based assay
|
Hepatitis C virus
|
86.7
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of 2'-dihalo ribonucleotide prodrugs with activity against hepatitis C virus.
Year : 2020
Volume : 28
Issue : 1
First Page : 115208
Last Page : 115208
Authors : Chris Krueger A, Chen HJ, Randolph JT, Brown BS, Halvorsen GT, Heyman HR, Li T, Marvin CC, Shanley JP, Voight EA, Bow DAJ, Van Handel C, Peterkin V, Carr RA, Stolarik D, Dekhtyar T, Irvin ML, Krishnan P, Henry RF, Wagner R, DeGoey DA.
Abstract : Hepatitis C virus (HCV) nucleoside inhibitors have been a key focus of nearly 2 decades of HCV drug research due to a high barrier to drug resistance and pan-genotypic activity profile provided by molecules in this drug class. Our investigations focused on several potent 2'-halogenated uridine-based HCV polymerase inhibitors, resulting in the discovery of novel 2'-deoxy-2'-dihalo-uridine analogs that are potent inhibitors in replicon assays for all genotypes. Further studies to improve in vivo performance of these nucleoside inhibitors identified aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs 18a and 18c, which provide high levels of the active triphosphate in dog liver. AIBEE prodrug 18c was compared with sofosbuvir (1) by co-dosing both compounds by oral administration in dog (5 mg/kg each) and measuring liver concentrations of the active triphosphate metabolite at both 4 and 24 h post dosing. In this study, 18c provided liver triphosphate concentrations that were 6-fold higher than sofosbuvir (1) at both biopsy time points, suggesting that 18c could be a highly effective agent for treating HCV infected patients in the clinic.
|
Antiviral activity against HCV genotype 1b Con1 over expressing CES1 infected in human HuH7 replicon cells assessed as inhibition of viral replication after 3 days by luciferase reporter gene assay
|
Hepatitis C virus
|
53.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of 2'-dihalo ribonucleotide prodrugs with activity against hepatitis C virus.
Year : 2020
Volume : 28
Issue : 1
First Page : 115208
Last Page : 115208
Authors : Chris Krueger A, Chen HJ, Randolph JT, Brown BS, Halvorsen GT, Heyman HR, Li T, Marvin CC, Shanley JP, Voight EA, Bow DAJ, Van Handel C, Peterkin V, Carr RA, Stolarik D, Dekhtyar T, Irvin ML, Krishnan P, Henry RF, Wagner R, DeGoey DA.
Abstract : Hepatitis C virus (HCV) nucleoside inhibitors have been a key focus of nearly 2 decades of HCV drug research due to a high barrier to drug resistance and pan-genotypic activity profile provided by molecules in this drug class. Our investigations focused on several potent 2'-halogenated uridine-based HCV polymerase inhibitors, resulting in the discovery of novel 2'-deoxy-2'-dihalo-uridine analogs that are potent inhibitors in replicon assays for all genotypes. Further studies to improve in vivo performance of these nucleoside inhibitors identified aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs 18a and 18c, which provide high levels of the active triphosphate in dog liver. AIBEE prodrug 18c was compared with sofosbuvir (1) by co-dosing both compounds by oral administration in dog (5 mg/kg each) and measuring liver concentrations of the active triphosphate metabolite at both 4 and 24 h post dosing. In this study, 18c provided liver triphosphate concentrations that were 6-fold higher than sofosbuvir (1) at both biopsy time points, suggesting that 18c could be a highly effective agent for treating HCV infected patients in the clinic.
|
Antiviral activity against HCV J6/JFH/JC1 infected in human Huh7.5 cells assessed as reduction in viral RNA levels incubated for 72 hrs by qRT-PCR analysis
|
Hepatitis C virus
|
46.0
nM
|
|
Journal : J Med Chem
Title : 2-((4-Arylpiperazin-1-yl)methyl)benzonitrile Derivatives as Orally Available Inhibitors of Hepatitis C Virus with a Novel Mechanism of Action.
Year : 2020
Volume : 63
Issue : 11
First Page : 5972
Last Page : 5989
Authors : Jiang X, Tan J, Wang Y, Chen J, Li J, Jiang Z, Quan Y, Jin J, Li Y, Cen S, Li Y, Peng Z, Li Z.
Abstract : Although the direct-acting antivirals revolutionized the hepatitis C virus (HCV) infection treatment in the last decade, more efforts are needed to reach the elimination of HCV in the absence of a vaccine. 4-(Piperazin-1-yl)-2-((p-tolylamino)methyl)-benzonitrile (1) is a modest HCV inhibitor identified from an in-house screening using a HCV-infected Huh7.5 cell culture. Starting from it, the chemical optimization afforded a new 2-((4-arylpiperazin-1-yl)methyl)benzonitrile scaffold with significantly increased antiviral activity against HCV. A highly effective HCV inhibitor, 35 (L0909, EC50 = 0.022 μM, SI > 600), was identified by the structure-activity relationship study. The biological study revealed that L0909 could block HCV replication by acting on the HCV entry stage. The high sensitivity to clinical resistant HCV mutants and synergistic effect with clinical drugs were observed for this compound. The further pharmaceutical studies demonstrated that L0909 is long-lasting, is orally available, and has low toxicity in vivo. These results show L0909 as a promising HCV entry inhibitor for single or combinational therapeutic potential.
|
Antiviral activity against HCV J6/JFH/JC1 infected in human Huh7.5 cells incubated for 72 hrs by In-Cell Western assay
|
Hepatitis C virus
|
104.0
nM
|
|
Journal : J Med Chem
Title : 2-((4-Arylpiperazin-1-yl)methyl)benzonitrile Derivatives as Orally Available Inhibitors of Hepatitis C Virus with a Novel Mechanism of Action.
Year : 2020
Volume : 63
Issue : 11
First Page : 5972
Last Page : 5989
Authors : Jiang X, Tan J, Wang Y, Chen J, Li J, Jiang Z, Quan Y, Jin J, Li Y, Cen S, Li Y, Peng Z, Li Z.
Abstract : Although the direct-acting antivirals revolutionized the hepatitis C virus (HCV) infection treatment in the last decade, more efforts are needed to reach the elimination of HCV in the absence of a vaccine. 4-(Piperazin-1-yl)-2-((p-tolylamino)methyl)-benzonitrile (1) is a modest HCV inhibitor identified from an in-house screening using a HCV-infected Huh7.5 cell culture. Starting from it, the chemical optimization afforded a new 2-((4-arylpiperazin-1-yl)methyl)benzonitrile scaffold with significantly increased antiviral activity against HCV. A highly effective HCV inhibitor, 35 (L0909, EC50 = 0.022 μM, SI > 600), was identified by the structure-activity relationship study. The biological study revealed that L0909 could block HCV replication by acting on the HCV entry stage. The high sensitivity to clinical resistant HCV mutants and synergistic effect with clinical drugs were observed for this compound. The further pharmaceutical studies demonstrated that L0909 is long-lasting, is orally available, and has low toxicity in vivo. These results show L0909 as a promising HCV entry inhibitor for single or combinational therapeutic potential.
|
Antiviral activity against wild type HCV by qRT-PCR analysis based by Reed-Muench method
|
Hepatitis C virus
|
29.4
nM
|
|
Journal : J Med Chem
Title : 2-((4-Arylpiperazin-1-yl)methyl)benzonitrile Derivatives as Orally Available Inhibitors of Hepatitis C Virus with a Novel Mechanism of Action.
Year : 2020
Volume : 63
Issue : 11
First Page : 5972
Last Page : 5989
Authors : Jiang X, Tan J, Wang Y, Chen J, Li J, Jiang Z, Quan Y, Jin J, Li Y, Cen S, Li Y, Peng Z, Li Z.
Abstract : Although the direct-acting antivirals revolutionized the hepatitis C virus (HCV) infection treatment in the last decade, more efforts are needed to reach the elimination of HCV in the absence of a vaccine. 4-(Piperazin-1-yl)-2-((p-tolylamino)methyl)-benzonitrile (1) is a modest HCV inhibitor identified from an in-house screening using a HCV-infected Huh7.5 cell culture. Starting from it, the chemical optimization afforded a new 2-((4-arylpiperazin-1-yl)methyl)benzonitrile scaffold with significantly increased antiviral activity against HCV. A highly effective HCV inhibitor, 35 (L0909, EC50 = 0.022 μM, SI > 600), was identified by the structure-activity relationship study. The biological study revealed that L0909 could block HCV replication by acting on the HCV entry stage. The high sensitivity to clinical resistant HCV mutants and synergistic effect with clinical drugs were observed for this compound. The further pharmaceutical studies demonstrated that L0909 is long-lasting, is orally available, and has low toxicity in vivo. These results show L0909 as a promising HCV entry inhibitor for single or combinational therapeutic potential.
|
Antiviral activity against HCV expressing NS5B S282T mutant by qRT-PCR analysis based by Reed-Muench method
|
Hepatitis C virus
|
147.9
nM
|
|
Journal : J Med Chem
Title : 2-((4-Arylpiperazin-1-yl)methyl)benzonitrile Derivatives as Orally Available Inhibitors of Hepatitis C Virus with a Novel Mechanism of Action.
Year : 2020
Volume : 63
Issue : 11
First Page : 5972
Last Page : 5989
Authors : Jiang X, Tan J, Wang Y, Chen J, Li J, Jiang Z, Quan Y, Jin J, Li Y, Cen S, Li Y, Peng Z, Li Z.
Abstract : Although the direct-acting antivirals revolutionized the hepatitis C virus (HCV) infection treatment in the last decade, more efforts are needed to reach the elimination of HCV in the absence of a vaccine. 4-(Piperazin-1-yl)-2-((p-tolylamino)methyl)-benzonitrile (1) is a modest HCV inhibitor identified from an in-house screening using a HCV-infected Huh7.5 cell culture. Starting from it, the chemical optimization afforded a new 2-((4-arylpiperazin-1-yl)methyl)benzonitrile scaffold with significantly increased antiviral activity against HCV. A highly effective HCV inhibitor, 35 (L0909, EC50 = 0.022 μM, SI > 600), was identified by the structure-activity relationship study. The biological study revealed that L0909 could block HCV replication by acting on the HCV entry stage. The high sensitivity to clinical resistant HCV mutants and synergistic effect with clinical drugs were observed for this compound. The further pharmaceutical studies demonstrated that L0909 is long-lasting, is orally available, and has low toxicity in vivo. These results show L0909 as a promising HCV entry inhibitor for single or combinational therapeutic potential.
|
Inhibition of NS5B polymerase in HCV genotype 1a H77 infected in human HuH7 replicon cells assessed as inhibition of viral replication after 3 days by luciferase reporter gene assay
|
Hepatitis C virus subtype 1a
|
155.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of 2-aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs for delivering nucleoside HCV NS5B polymerase inhibitors.
Year : 2020
Volume : 30
Issue : 7
First Page : 126986
Last Page : 126986
Authors : Randolph JT, Li T, Chris Krueger A, Heyman HR, Chen HJ, Bow DAJ, Van Handel C, Peterkin V, Carr RA, Stolarik D, Dekhtyar T, Irvin M, Krishnan P, Wagner R, DeGoey DA.
Abstract : Our HCV research program investigated novel 2'-dihalogenated nucleoside HCV polymerase inhibitors and identified compound 1, a 5'-phosphoramidate prodrug of 2'-deoxy-2'-α-bromo-β-chloro uridine. Although 1 had a favorable in vitro activity profile in HCV replicons, oral dosing in dog resulted in low levels of the active 5'-triphosphate (TP) in liver. Metabolism studies using human hepatocytes provided a simple assay for screening alternative phosphoramidate prodrug analogs. Compounds that produced high TP concentrations in hepatocytes were tested in dog liver biopsy studies. This method identified 2-aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrug 14, which provided 100-fold higher TP concentrations in dog liver in comparison to 1 (4 and 24 h after 5 mg/kg oral dose).
|
Inhibition of NS5B polymerase in HCV genotype 1b Con1 infected in human HuH7 replicon cells assessed as inhibition of viral replication after 3 days by luciferase reporter gene assay
|
Hepatitis C virus subtype 1b
|
230.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of 2-aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs for delivering nucleoside HCV NS5B polymerase inhibitors.
Year : 2020
Volume : 30
Issue : 7
First Page : 126986
Last Page : 126986
Authors : Randolph JT, Li T, Chris Krueger A, Heyman HR, Chen HJ, Bow DAJ, Van Handel C, Peterkin V, Carr RA, Stolarik D, Dekhtyar T, Irvin M, Krishnan P, Wagner R, DeGoey DA.
Abstract : Our HCV research program investigated novel 2'-dihalogenated nucleoside HCV polymerase inhibitors and identified compound 1, a 5'-phosphoramidate prodrug of 2'-deoxy-2'-α-bromo-β-chloro uridine. Although 1 had a favorable in vitro activity profile in HCV replicons, oral dosing in dog resulted in low levels of the active 5'-triphosphate (TP) in liver. Metabolism studies using human hepatocytes provided a simple assay for screening alternative phosphoramidate prodrug analogs. Compounds that produced high TP concentrations in hepatocytes were tested in dog liver biopsy studies. This method identified 2-aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrug 14, which provided 100-fold higher TP concentrations in dog liver in comparison to 1 (4 and 24 h after 5 mg/kg oral dose).
|
Antiviral activity against HCV subtype 1b infected in human HuH-7-Luc/Neo-ET cells by luciferase replicon-reporter gene assay
|
Hepatitis C virus
|
30.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and biological evaluation of 5'-C-methyl nucleotide prodrugs for treating HCV infections.
Year : 2020
Volume : 30
Issue : 23
First Page : 127539
Last Page : 127539
Authors : Dasari M,Ma P,Pelly SC,Sharma SK,Liotta DC
Abstract : Nucleotide prodrugs are of great clinical interest for treating a variety of viral infections due to their ability to target tissues selectively and to deliver relatively high concentrations of the active nucleotide metabolite intracellularly. However, their clinical successes have been limited, oftentimes due to unwanted in vivo metabolic processes that reduce the quantities of nucleoside triphosphate that reach the site of action. In an attempt to circumvent this, we designed novel nucleosides that incorporate a sterically bulky group at the 5'-carbon of the phosphoester prodrug, which we reasoned would reduce the amounts of non-productive PO bond cleavage back to the corresponding nucleoside by nucleotidases. Molecular docking studies with the NS5B HCV polymerase suggested that a nucleotide containing a 5'-methyl group could be accommodated. Therefore, we synthesized mono- and diphosphate prodrugs of 2',5'-C-dimethyluridine stereoselectively and evaluated their cytotoxicity and anti-HCV activity in the HCV replicon assay. All four prodrugs exhibited anti-HCV activity with IC values in the single digit micromolar concentrations, with the 5'(R)-C-methyl prodrug displaying superior potency relative to its 5'(S)-C-methyl counterpart. However, when compared to the unmethylated prodrug, the potency is poorer. The poorer potency of these prodrugs may be due to unfavorable steric interactions of the 5'-C-methyl group in the active sites of the kinases that catalyze the formation of active triphosphate metabolite.
|
Antiviral activity against HCV J6/JFH/JC1 harboring S282T mutant infected in human Huh7.5 cells assessed as inhibition of viral replication measured after 72 hrs by qRT-PCR analysis
|
Hepatitis C virus
|
290.0
nM
|
|
Journal : J Med Chem
Title : Design and Synthesis of Cajanine Analogues against Hepatitis C Virus through Down-Regulating Host Chondroitin Sulfate N-Acetylgalactosaminyltransferase 1.
Year : 2016
Volume : 59
Issue : 22.0
First Page : 10268
Last Page : 10284
Authors : Ji XY,Chen JH,Zheng GH,Huang MH,Zhang L,Yi H,Jin J,Jiang JD,Peng ZG,Li ZR
Abstract : There still remains a need to develop new anti-HCV agents with distinct mechanism of action (MOA) due to the occurrence of resistance to direct-acting antiviral agents (DAAs). Cajanine, a stilbenic component isolated from Cajanus cajan L., was identified as a potent HCV inhibitor by phenotypic screening in this work (EC = 3.17 ± 0.75 μM). The intensive structure optimization provided significant insights into the structure-activity relationships. Furthermore, the MOA study revealed that cajanine inhibited HCV replications via down-regulating a cellular protein chondroitin sulfate N-acetylgalactosaminyltransferase 1. In consistency with this host-targeting mechanism, cajanine showed the similar magnitude of inhibitory activity against both drug-resistant and wild-type HCV and synergistically inhibited HCV replication with approved DAAs. Taken together, our study not only presented cajanine derivatives as a novel class of anti-HCV agents but also discovered a promising anti-HCV target to combat drug resistance.
|
Antiviral activity against wild-type HCV J6/JFH/JC1 infected in human Huh7.5 cells assessed as inhibition of viral replication measured after 72 hrs by qRT-PCR analysis
|
Hepatitis C virus
|
64.0
nM
|
|
Journal : J Med Chem
Title : Design and Synthesis of Cajanine Analogues against Hepatitis C Virus through Down-Regulating Host Chondroitin Sulfate N-Acetylgalactosaminyltransferase 1.
Year : 2016
Volume : 59
Issue : 22.0
First Page : 10268
Last Page : 10284
Authors : Ji XY,Chen JH,Zheng GH,Huang MH,Zhang L,Yi H,Jin J,Jiang JD,Peng ZG,Li ZR
Abstract : There still remains a need to develop new anti-HCV agents with distinct mechanism of action (MOA) due to the occurrence of resistance to direct-acting antiviral agents (DAAs). Cajanine, a stilbenic component isolated from Cajanus cajan L., was identified as a potent HCV inhibitor by phenotypic screening in this work (EC = 3.17 ± 0.75 μM). The intensive structure optimization provided significant insights into the structure-activity relationships. Furthermore, the MOA study revealed that cajanine inhibited HCV replications via down-regulating a cellular protein chondroitin sulfate N-acetylgalactosaminyltransferase 1. In consistency with this host-targeting mechanism, cajanine showed the similar magnitude of inhibitory activity against both drug-resistant and wild-type HCV and synergistically inhibited HCV replication with approved DAAs. Taken together, our study not only presented cajanine derivatives as a novel class of anti-HCV agents but also discovered a promising anti-HCV target to combat drug resistance.
|
Antiviral activity against HCV infected in human Huh7.5 cells incubated for 72 hrs by in-cell western assay
|
Hepatitis C virus
|
82.0
nM
|
|
|
Antiviral activity against HCVcc infected in human Huh7.5 cells assessed as inhibition of viral replication
|
Hepatitis C virus
|
128.66
nM
|
|
|
Antiviral activity against HCV infected in human Huh7.5 cells carrying HCV subgenomic replicons assessed as inhibition of viral replication
|
Hepatitis C virus
|
180.0
nM
|
|
