|
Inhibition of Hepatitis C virus (isolate BK) genotype 1b NS3/4a protease expressed in Escherichia coli by time-resolved fluorescence analysis
|
Hepatitis C virus (isolate BK)
|
0.02
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor.
Year : 2012
Volume : 3
Issue : 4
First Page : 332
Last Page : 336
Authors : Harper S, McCauley JA, Rudd MT, Ferrara M, DiFilippo M, Crescenzi B, Koch U, Petrocchi A, Holloway MK, Butcher JW, Romano JJ, Bush KJ, Gilbert KF, McIntyre CJ, Nguyen KT, Nizi E, Carroll SS, Ludmerer SW, Burlein C, DiMuzio JM, Graham DJ, McHale CM, Stahlhut MW, Olsen DB, Monteagudo E, Cianetti S, Giuliano C, Pucci V, Trainor N, Fandozzi CM, Rowley M, Coleman PJ, Vacca JP, Summa V, Liverton NJ.
Abstract : A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.
|
Inhibition of Hepatitis C virus (isolate NZL1) genotype 3a NS3/4a protease expressed in Escherichia coli by time-resolved fluorescence analysis
|
Hepatitis C virus (isolate NZL1)
|
0.7
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor.
Year : 2012
Volume : 3
Issue : 4
First Page : 332
Last Page : 336
Authors : Harper S, McCauley JA, Rudd MT, Ferrara M, DiFilippo M, Crescenzi B, Koch U, Petrocchi A, Holloway MK, Butcher JW, Romano JJ, Bush KJ, Gilbert KF, McIntyre CJ, Nguyen KT, Nizi E, Carroll SS, Ludmerer SW, Burlein C, DiMuzio JM, Graham DJ, McHale CM, Stahlhut MW, Olsen DB, Monteagudo E, Cianetti S, Giuliano C, Pucci V, Trainor N, Fandozzi CM, Rowley M, Coleman PJ, Vacca JP, Summa V, Liverton NJ.
Abstract : A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.
|
Inhibition of Hepatitis C virus (isolate BK) genotype 1b NS3/4a protease R155K mutant expressed in Escherichia coli by time-resolved fluorescence analysis
|
Hepatitis C virus (isolate BK)
|
0.07
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor.
Year : 2012
Volume : 3
Issue : 4
First Page : 332
Last Page : 336
Authors : Harper S, McCauley JA, Rudd MT, Ferrara M, DiFilippo M, Crescenzi B, Koch U, Petrocchi A, Holloway MK, Butcher JW, Romano JJ, Bush KJ, Gilbert KF, McIntyre CJ, Nguyen KT, Nizi E, Carroll SS, Ludmerer SW, Burlein C, DiMuzio JM, Graham DJ, McHale CM, Stahlhut MW, Olsen DB, Monteagudo E, Cianetti S, Giuliano C, Pucci V, Trainor N, Fandozzi CM, Rowley M, Coleman PJ, Vacca JP, Summa V, Liverton NJ.
Abstract : A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.
|
Inhibition of Hepatitis C virus (isolate BK) genotype 1b NS3/4a protease A156T mutant expressed in Escherichia coli by time-resolved fluorescence analysis
|
Hepatitis C virus (isolate BK)
|
5.3
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor.
Year : 2012
Volume : 3
Issue : 4
First Page : 332
Last Page : 336
Authors : Harper S, McCauley JA, Rudd MT, Ferrara M, DiFilippo M, Crescenzi B, Koch U, Petrocchi A, Holloway MK, Butcher JW, Romano JJ, Bush KJ, Gilbert KF, McIntyre CJ, Nguyen KT, Nizi E, Carroll SS, Ludmerer SW, Burlein C, DiMuzio JM, Graham DJ, McHale CM, Stahlhut MW, Olsen DB, Monteagudo E, Cianetti S, Giuliano C, Pucci V, Trainor N, Fandozzi CM, Rowley M, Coleman PJ, Vacca JP, Summa V, Liverton NJ.
Abstract : A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.
|
Inhibition of Hepatitis C virus (isolate BK) genotype 1b NS3/4a protease A156V mutant expressed in Escherichia coli by time-resolved fluorescence analysis
|
Hepatitis C virus (isolate BK)
|
12.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor.
Year : 2012
Volume : 3
Issue : 4
First Page : 332
Last Page : 336
Authors : Harper S, McCauley JA, Rudd MT, Ferrara M, DiFilippo M, Crescenzi B, Koch U, Petrocchi A, Holloway MK, Butcher JW, Romano JJ, Bush KJ, Gilbert KF, McIntyre CJ, Nguyen KT, Nizi E, Carroll SS, Ludmerer SW, Burlein C, DiMuzio JM, Graham DJ, McHale CM, Stahlhut MW, Olsen DB, Monteagudo E, Cianetti S, Giuliano C, Pucci V, Trainor N, Fandozzi CM, Rowley M, Coleman PJ, Vacca JP, Summa V, Liverton NJ.
Abstract : A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.
|
Inhibition of Hepatitis C virus (isolate BK) genotype 1b NS3/4a protease D168V mutant expressed in Escherichia coli by time-resolved fluorescence analysis
|
Hepatitis C virus (isolate BK)
|
0.14
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor.
Year : 2012
Volume : 3
Issue : 4
First Page : 332
Last Page : 336
Authors : Harper S, McCauley JA, Rudd MT, Ferrara M, DiFilippo M, Crescenzi B, Koch U, Petrocchi A, Holloway MK, Butcher JW, Romano JJ, Bush KJ, Gilbert KF, McIntyre CJ, Nguyen KT, Nizi E, Carroll SS, Ludmerer SW, Burlein C, DiMuzio JM, Graham DJ, McHale CM, Stahlhut MW, Olsen DB, Monteagudo E, Cianetti S, Giuliano C, Pucci V, Trainor N, Fandozzi CM, Rowley M, Coleman PJ, Vacca JP, Summa V, Liverton NJ.
Abstract : A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.
|
Antiviral activity against Hepatitis C virus (isolate Con1) genotype 1b infected in human HuH7 cells assessed as inhibition of viral replication after 24 hrs in presence of 50% NHS
|
Hepatitis C virus (isolate Con1)
|
7.4
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor.
Year : 2012
Volume : 3
Issue : 4
First Page : 332
Last Page : 336
Authors : Harper S, McCauley JA, Rudd MT, Ferrara M, DiFilippo M, Crescenzi B, Koch U, Petrocchi A, Holloway MK, Butcher JW, Romano JJ, Bush KJ, Gilbert KF, McIntyre CJ, Nguyen KT, Nizi E, Carroll SS, Ludmerer SW, Burlein C, DiMuzio JM, Graham DJ, McHale CM, Stahlhut MW, Olsen DB, Monteagudo E, Cianetti S, Giuliano C, Pucci V, Trainor N, Fandozzi CM, Rowley M, Coleman PJ, Vacca JP, Summa V, Liverton NJ.
Abstract : A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.
|
Antiviral activity against Hepatitis C virus genotype 1a infected in human HuH7 cells assessed as inhibition of viral replication after 24 hrs presence of 40% NHS
|
Hepatitis C virus subtype 1a
|
7.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor.
Year : 2012
Volume : 3
Issue : 4
First Page : 332
Last Page : 336
Authors : Harper S, McCauley JA, Rudd MT, Ferrara M, DiFilippo M, Crescenzi B, Koch U, Petrocchi A, Holloway MK, Butcher JW, Romano JJ, Bush KJ, Gilbert KF, McIntyre CJ, Nguyen KT, Nizi E, Carroll SS, Ludmerer SW, Burlein C, DiMuzio JM, Graham DJ, McHale CM, Stahlhut MW, Olsen DB, Monteagudo E, Cianetti S, Giuliano C, Pucci V, Trainor N, Fandozzi CM, Rowley M, Coleman PJ, Vacca JP, Summa V, Liverton NJ.
Abstract : A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.
|
Inhibition of Hepatitis C virus genotype 1b NS3/4A protease D168Y mutant assessed as substrate cleavage using Ac-C(Eu)DDMEEAbu(COO)ASK(QSY7)-amide as substrate incubated for 30 mins prior to substrate addition by time-resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
0.14
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Novel Quinoline-Based P2-P4 Macrocyclic Derivatives As Pan-Genotypic HCV NS3/4a Protease Inhibitors.
Year : 2014
Volume : 5
Issue : 3
First Page : 264
Last Page : 269
Authors : Shah U, Jayne C, Chackalamannil S, Velázquez F, Guo Z, Buevich A, Howe JA, Chase R, Soriano A, Agrawal S, Rudd MT, McCauley JA, Liverton NJ, Romano J, Bush K, Coleman PJ, Grisé-Bard C, Brochu MC, Charron S, Aulakh V, Bachand B, Beaulieu P, Zaghdane H, Bhat S, Han Y, Vacca JP, Davies IW, Weber AE, Venkatraman S.
Abstract : We have previously reported the discovery of our P2-P4 macrocyclic HCV NS3/4a protease inhibitor MK-5172, which in combination with the NS5a inhibitor MK-8742 recently received a breakthrough therapy designation from the US FDA for treatment of chronic HCV infection. Our goal for the next generation NS3/4a inhibitor was to achieve pan-genotypic activity while retaining the pharmacokinetic profile of MK-5172. One of the areas for follow-up investigation involved replacement of the quinoxaline moiety in MK-5172 with a quinoline and studying the effect of substitution at 4-position of the quinoline. The rationale for this effort was based on molecular modeling, which indicated that such modifications would improve interactions with the S2 subsite, in particular with D79. We wish to report herein the discovery of highly potent inhibitors with pan-genotypic activity and an improved profile over MK-5172, especially against gt-3a and A156 mutants.
|
Inhibition of Hepatitis C virus genotype 1b NS3/4A protease A156V mutant assessed as substrate cleavage using Ac-C(Eu)DDMEEAbu(COO)ASK(QSY7)-amide as substrate incubated for 30 mins prior to substrate addition by time-resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
12.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Novel Quinoline-Based P2-P4 Macrocyclic Derivatives As Pan-Genotypic HCV NS3/4a Protease Inhibitors.
Year : 2014
Volume : 5
Issue : 3
First Page : 264
Last Page : 269
Authors : Shah U, Jayne C, Chackalamannil S, Velázquez F, Guo Z, Buevich A, Howe JA, Chase R, Soriano A, Agrawal S, Rudd MT, McCauley JA, Liverton NJ, Romano J, Bush K, Coleman PJ, Grisé-Bard C, Brochu MC, Charron S, Aulakh V, Bachand B, Beaulieu P, Zaghdane H, Bhat S, Han Y, Vacca JP, Davies IW, Weber AE, Venkatraman S.
Abstract : We have previously reported the discovery of our P2-P4 macrocyclic HCV NS3/4a protease inhibitor MK-5172, which in combination with the NS5a inhibitor MK-8742 recently received a breakthrough therapy designation from the US FDA for treatment of chronic HCV infection. Our goal for the next generation NS3/4a inhibitor was to achieve pan-genotypic activity while retaining the pharmacokinetic profile of MK-5172. One of the areas for follow-up investigation involved replacement of the quinoxaline moiety in MK-5172 with a quinoline and studying the effect of substitution at 4-position of the quinoline. The rationale for this effort was based on molecular modeling, which indicated that such modifications would improve interactions with the S2 subsite, in particular with D79. We wish to report herein the discovery of highly potent inhibitors with pan-genotypic activity and an improved profile over MK-5172, especially against gt-3a and A156 mutants.
|
Inhibition of Hepatitis C virus genotype 1b NS3/4A protease A156T mutant assessed as substrate cleavage using Ac-C(Eu)DDMEEAbu(COO)ASK(QSY7)-amide as substrate incubated for 30 mins prior to substrate addition by time-resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
5.3
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Novel Quinoline-Based P2-P4 Macrocyclic Derivatives As Pan-Genotypic HCV NS3/4a Protease Inhibitors.
Year : 2014
Volume : 5
Issue : 3
First Page : 264
Last Page : 269
Authors : Shah U, Jayne C, Chackalamannil S, Velázquez F, Guo Z, Buevich A, Howe JA, Chase R, Soriano A, Agrawal S, Rudd MT, McCauley JA, Liverton NJ, Romano J, Bush K, Coleman PJ, Grisé-Bard C, Brochu MC, Charron S, Aulakh V, Bachand B, Beaulieu P, Zaghdane H, Bhat S, Han Y, Vacca JP, Davies IW, Weber AE, Venkatraman S.
Abstract : We have previously reported the discovery of our P2-P4 macrocyclic HCV NS3/4a protease inhibitor MK-5172, which in combination with the NS5a inhibitor MK-8742 recently received a breakthrough therapy designation from the US FDA for treatment of chronic HCV infection. Our goal for the next generation NS3/4a inhibitor was to achieve pan-genotypic activity while retaining the pharmacokinetic profile of MK-5172. One of the areas for follow-up investigation involved replacement of the quinoxaline moiety in MK-5172 with a quinoline and studying the effect of substitution at 4-position of the quinoline. The rationale for this effort was based on molecular modeling, which indicated that such modifications would improve interactions with the S2 subsite, in particular with D79. We wish to report herein the discovery of highly potent inhibitors with pan-genotypic activity and an improved profile over MK-5172, especially against gt-3a and A156 mutants.
|
Inhibition of Hepatitis C virus genotype 1b NS3/4A protease R155K mutant assessed as substrate cleavage using Ac-C(Eu)DDMEEAbu(COO)ASK(QSY7)-amide as substrate incubated for 30 mins prior to substrate addition by time-resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
0.07
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Novel Quinoline-Based P2-P4 Macrocyclic Derivatives As Pan-Genotypic HCV NS3/4a Protease Inhibitors.
Year : 2014
Volume : 5
Issue : 3
First Page : 264
Last Page : 269
Authors : Shah U, Jayne C, Chackalamannil S, Velázquez F, Guo Z, Buevich A, Howe JA, Chase R, Soriano A, Agrawal S, Rudd MT, McCauley JA, Liverton NJ, Romano J, Bush K, Coleman PJ, Grisé-Bard C, Brochu MC, Charron S, Aulakh V, Bachand B, Beaulieu P, Zaghdane H, Bhat S, Han Y, Vacca JP, Davies IW, Weber AE, Venkatraman S.
Abstract : We have previously reported the discovery of our P2-P4 macrocyclic HCV NS3/4a protease inhibitor MK-5172, which in combination with the NS5a inhibitor MK-8742 recently received a breakthrough therapy designation from the US FDA for treatment of chronic HCV infection. Our goal for the next generation NS3/4a inhibitor was to achieve pan-genotypic activity while retaining the pharmacokinetic profile of MK-5172. One of the areas for follow-up investigation involved replacement of the quinoxaline moiety in MK-5172 with a quinoline and studying the effect of substitution at 4-position of the quinoline. The rationale for this effort was based on molecular modeling, which indicated that such modifications would improve interactions with the S2 subsite, in particular with D79. We wish to report herein the discovery of highly potent inhibitors with pan-genotypic activity and an improved profile over MK-5172, especially against gt-3a and A156 mutants.
|
Antiviral activity against Hepatitis C virus genotype 3a infected in HuH7 cells assessed as reduction in replicon RNA level after 72 hrs by TaqMan-based RT-PCR analysis in presence of 10% FBS
|
Hepatitis C virus subtype 3a
|
13.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Novel Quinoline-Based P2-P4 Macrocyclic Derivatives As Pan-Genotypic HCV NS3/4a Protease Inhibitors.
Year : 2014
Volume : 5
Issue : 3
First Page : 264
Last Page : 269
Authors : Shah U, Jayne C, Chackalamannil S, Velázquez F, Guo Z, Buevich A, Howe JA, Chase R, Soriano A, Agrawal S, Rudd MT, McCauley JA, Liverton NJ, Romano J, Bush K, Coleman PJ, Grisé-Bard C, Brochu MC, Charron S, Aulakh V, Bachand B, Beaulieu P, Zaghdane H, Bhat S, Han Y, Vacca JP, Davies IW, Weber AE, Venkatraman S.
Abstract : We have previously reported the discovery of our P2-P4 macrocyclic HCV NS3/4a protease inhibitor MK-5172, which in combination with the NS5a inhibitor MK-8742 recently received a breakthrough therapy designation from the US FDA for treatment of chronic HCV infection. Our goal for the next generation NS3/4a inhibitor was to achieve pan-genotypic activity while retaining the pharmacokinetic profile of MK-5172. One of the areas for follow-up investigation involved replacement of the quinoxaline moiety in MK-5172 with a quinoline and studying the effect of substitution at 4-position of the quinoline. The rationale for this effort was based on molecular modeling, which indicated that such modifications would improve interactions with the S2 subsite, in particular with D79. We wish to report herein the discovery of highly potent inhibitors with pan-genotypic activity and an improved profile over MK-5172, especially against gt-3a and A156 mutants.
|
Antiviral activity against Hepatitis C virus genotype 1b infected in HuH7 cells assessed as reduction in replicon RNA level after 72 hrs by TaqMan-based RT-PCR analysis in presence of 10% FBS
|
Hepatitis C virus subtype 1b
|
1.5
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Novel Quinoline-Based P2-P4 Macrocyclic Derivatives As Pan-Genotypic HCV NS3/4a Protease Inhibitors.
Year : 2014
Volume : 5
Issue : 3
First Page : 264
Last Page : 269
Authors : Shah U, Jayne C, Chackalamannil S, Velázquez F, Guo Z, Buevich A, Howe JA, Chase R, Soriano A, Agrawal S, Rudd MT, McCauley JA, Liverton NJ, Romano J, Bush K, Coleman PJ, Grisé-Bard C, Brochu MC, Charron S, Aulakh V, Bachand B, Beaulieu P, Zaghdane H, Bhat S, Han Y, Vacca JP, Davies IW, Weber AE, Venkatraman S.
Abstract : We have previously reported the discovery of our P2-P4 macrocyclic HCV NS3/4a protease inhibitor MK-5172, which in combination with the NS5a inhibitor MK-8742 recently received a breakthrough therapy designation from the US FDA for treatment of chronic HCV infection. Our goal for the next generation NS3/4a inhibitor was to achieve pan-genotypic activity while retaining the pharmacokinetic profile of MK-5172. One of the areas for follow-up investigation involved replacement of the quinoxaline moiety in MK-5172 with a quinoline and studying the effect of substitution at 4-position of the quinoline. The rationale for this effort was based on molecular modeling, which indicated that such modifications would improve interactions with the S2 subsite, in particular with D79. We wish to report herein the discovery of highly potent inhibitors with pan-genotypic activity and an improved profile over MK-5172, especially against gt-3a and A156 mutants.
|
Inhibition of Hepatitis C virus genotype 3a NS3/4A protease assessed as substrate cleavage using Ac-C(Eu)DDMEEAbu(COO)ASK(QSY7)-amide as substrate incubated for 30 mins prior to substrate addition by time-resolved fluorescence assay
|
Hepatitis C virus subtype 3a
|
0.7
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Novel Quinoline-Based P2-P4 Macrocyclic Derivatives As Pan-Genotypic HCV NS3/4a Protease Inhibitors.
Year : 2014
Volume : 5
Issue : 3
First Page : 264
Last Page : 269
Authors : Shah U, Jayne C, Chackalamannil S, Velázquez F, Guo Z, Buevich A, Howe JA, Chase R, Soriano A, Agrawal S, Rudd MT, McCauley JA, Liverton NJ, Romano J, Bush K, Coleman PJ, Grisé-Bard C, Brochu MC, Charron S, Aulakh V, Bachand B, Beaulieu P, Zaghdane H, Bhat S, Han Y, Vacca JP, Davies IW, Weber AE, Venkatraman S.
Abstract : We have previously reported the discovery of our P2-P4 macrocyclic HCV NS3/4a protease inhibitor MK-5172, which in combination with the NS5a inhibitor MK-8742 recently received a breakthrough therapy designation from the US FDA for treatment of chronic HCV infection. Our goal for the next generation NS3/4a inhibitor was to achieve pan-genotypic activity while retaining the pharmacokinetic profile of MK-5172. One of the areas for follow-up investigation involved replacement of the quinoxaline moiety in MK-5172 with a quinoline and studying the effect of substitution at 4-position of the quinoline. The rationale for this effort was based on molecular modeling, which indicated that such modifications would improve interactions with the S2 subsite, in particular with D79. We wish to report herein the discovery of highly potent inhibitors with pan-genotypic activity and an improved profile over MK-5172, especially against gt-3a and A156 mutants.
|
Inhibition of Hepatitis C virus genotype 1b NS3/4A protease assessed as substrate cleavage using Ac-C(Eu)DDMEEAbu(COO)ASK(QSY7)-amide as substrate incubated for 30 mins prior to substrate addition by time-resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
0.02
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Novel Quinoline-Based P2-P4 Macrocyclic Derivatives As Pan-Genotypic HCV NS3/4a Protease Inhibitors.
Year : 2014
Volume : 5
Issue : 3
First Page : 264
Last Page : 269
Authors : Shah U, Jayne C, Chackalamannil S, Velázquez F, Guo Z, Buevich A, Howe JA, Chase R, Soriano A, Agrawal S, Rudd MT, McCauley JA, Liverton NJ, Romano J, Bush K, Coleman PJ, Grisé-Bard C, Brochu MC, Charron S, Aulakh V, Bachand B, Beaulieu P, Zaghdane H, Bhat S, Han Y, Vacca JP, Davies IW, Weber AE, Venkatraman S.
Abstract : We have previously reported the discovery of our P2-P4 macrocyclic HCV NS3/4a protease inhibitor MK-5172, which in combination with the NS5a inhibitor MK-8742 recently received a breakthrough therapy designation from the US FDA for treatment of chronic HCV infection. Our goal for the next generation NS3/4a inhibitor was to achieve pan-genotypic activity while retaining the pharmacokinetic profile of MK-5172. One of the areas for follow-up investigation involved replacement of the quinoxaline moiety in MK-5172 with a quinoline and studying the effect of substitution at 4-position of the quinoline. The rationale for this effort was based on molecular modeling, which indicated that such modifications would improve interactions with the S2 subsite, in particular with D79. We wish to report herein the discovery of highly potent inhibitors with pan-genotypic activity and an improved profile over MK-5172, especially against gt-3a and A156 mutants.
|
Antiviral activity against HCV genotype 1a infected in human HuH7 cells assessed as inhibition of viral replication after 72 hrs by RT-PCR method
|
Hepatitis C virus subtype 1a
|
0.3
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor.
Year : 2016
Volume : 7
Issue : 1
First Page : 111
Last Page : 116
Authors : Neelamkavil SF, Agrawal S, Bara T, Bennett C, Bhat S, Biswas D, Brockunier L, Buist N, Burnette D, Cartwright M, Chackalamannil S, Chase R, Chelliah M, Chen A, Clasby M, Colandrea VJ, Davies IW, Eagen K, Guo Z, Han Y, Howe J, Jayne C, Josien H, Kargman S, Marcantonio K, Miao S, Miller R, Nolting A, Pinto P, Rajagopalan M, Ruck RT, Shah U, Soriano A, Sperbeck D, Velazquez F, Wu J, Xia Y, Venkatraman S.
Abstract : We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.
|
Inhibition of HCV genotype 1b full length NS3/4A protease using Ac-C(Eu)DDMEEAbu[COO]ASK(QSY7)-amide as substrate preincubated for 30 mins followed by substrate addition measured after 2.5 hrs by TRF assay
|
Hepatitis C virus subtype 1b
|
0.004
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor.
Year : 2016
Volume : 7
Issue : 1
First Page : 111
Last Page : 116
Authors : Neelamkavil SF, Agrawal S, Bara T, Bennett C, Bhat S, Biswas D, Brockunier L, Buist N, Burnette D, Cartwright M, Chackalamannil S, Chase R, Chelliah M, Chen A, Clasby M, Colandrea VJ, Davies IW, Eagen K, Guo Z, Han Y, Howe J, Jayne C, Josien H, Kargman S, Marcantonio K, Miao S, Miller R, Nolting A, Pinto P, Rajagopalan M, Ruck RT, Shah U, Soriano A, Sperbeck D, Velazquez F, Wu J, Xia Y, Venkatraman S.
Abstract : We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.
|
Inhibition of HCV genotype 3a full length NS3/4A protease using Ac-C(Eu)DDMEEAbu[COO]ASK(QSY7)-amide as substrate preincubated for 30 mins followed by substrate addition measured after 2.5 hrs by TRF assay
|
Hepatitis C virus subtype 3a
|
0.69
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor.
Year : 2016
Volume : 7
Issue : 1
First Page : 111
Last Page : 116
Authors : Neelamkavil SF, Agrawal S, Bara T, Bennett C, Bhat S, Biswas D, Brockunier L, Buist N, Burnette D, Cartwright M, Chackalamannil S, Chase R, Chelliah M, Chen A, Clasby M, Colandrea VJ, Davies IW, Eagen K, Guo Z, Han Y, Howe J, Jayne C, Josien H, Kargman S, Marcantonio K, Miao S, Miller R, Nolting A, Pinto P, Rajagopalan M, Ruck RT, Shah U, Soriano A, Sperbeck D, Velazquez F, Wu J, Xia Y, Venkatraman S.
Abstract : We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.
|
Inhibition of HCV genotype 1b NS3/4A protease R155K mutant using Ac-C(Eu)DDMEEAbu[COO]ASK(QSY7)-amide as substrate preincubated for 30 mins followed by substrate addition measured after 2.5 hrs by TRF assay
|
Hepatitis C virus subtype 1b
|
0.021
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor.
Year : 2016
Volume : 7
Issue : 1
First Page : 111
Last Page : 116
Authors : Neelamkavil SF, Agrawal S, Bara T, Bennett C, Bhat S, Biswas D, Brockunier L, Buist N, Burnette D, Cartwright M, Chackalamannil S, Chase R, Chelliah M, Chen A, Clasby M, Colandrea VJ, Davies IW, Eagen K, Guo Z, Han Y, Howe J, Jayne C, Josien H, Kargman S, Marcantonio K, Miao S, Miller R, Nolting A, Pinto P, Rajagopalan M, Ruck RT, Shah U, Soriano A, Sperbeck D, Velazquez F, Wu J, Xia Y, Venkatraman S.
Abstract : We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.
|
Inhibition of HCV genotype 1b NS3/4A protease A156T mutant using Ac-C(Eu)DDMEEAbu[COO]ASK(QSY7)-amide as substrate preincubated for 30 mins followed by substrate addition measured after 2.5 hrs by TRF assay
|
Hepatitis C virus subtype 1b
|
3.917
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor.
Year : 2016
Volume : 7
Issue : 1
First Page : 111
Last Page : 116
Authors : Neelamkavil SF, Agrawal S, Bara T, Bennett C, Bhat S, Biswas D, Brockunier L, Buist N, Burnette D, Cartwright M, Chackalamannil S, Chase R, Chelliah M, Chen A, Clasby M, Colandrea VJ, Davies IW, Eagen K, Guo Z, Han Y, Howe J, Jayne C, Josien H, Kargman S, Marcantonio K, Miao S, Miller R, Nolting A, Pinto P, Rajagopalan M, Ruck RT, Shah U, Soriano A, Sperbeck D, Velazquez F, Wu J, Xia Y, Venkatraman S.
Abstract : We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.
|
Inhibition of HCV genotype 1b NS3/4A protease A156V mutant using Ac-C(Eu)DDMEEAbu[COO]ASK(QSY7)-amide as substrate preincubated for 30 mins followed by substrate addition measured after 2.5 hrs by TRF assay
|
Hepatitis C virus subtype 1b
|
5.511
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor.
Year : 2016
Volume : 7
Issue : 1
First Page : 111
Last Page : 116
Authors : Neelamkavil SF, Agrawal S, Bara T, Bennett C, Bhat S, Biswas D, Brockunier L, Buist N, Burnette D, Cartwright M, Chackalamannil S, Chase R, Chelliah M, Chen A, Clasby M, Colandrea VJ, Davies IW, Eagen K, Guo Z, Han Y, Howe J, Jayne C, Josien H, Kargman S, Marcantonio K, Miao S, Miller R, Nolting A, Pinto P, Rajagopalan M, Ruck RT, Shah U, Soriano A, Sperbeck D, Velazquez F, Wu J, Xia Y, Venkatraman S.
Abstract : We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.
|
Inhibition of HCV genotype 1b NS3/4A protease D168Y mutant using Ac-C(Eu)DDMEEAbu[COO]ASK(QSY7)-amide as substrate preincubated for 30 mins followed by substrate addition measured after 2.5 hrs by TRF assay
|
Hepatitis C virus subtype 1b
|
0.105
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor.
Year : 2016
Volume : 7
Issue : 1
First Page : 111
Last Page : 116
Authors : Neelamkavil SF, Agrawal S, Bara T, Bennett C, Bhat S, Biswas D, Brockunier L, Buist N, Burnette D, Cartwright M, Chackalamannil S, Chase R, Chelliah M, Chen A, Clasby M, Colandrea VJ, Davies IW, Eagen K, Guo Z, Han Y, Howe J, Jayne C, Josien H, Kargman S, Marcantonio K, Miao S, Miller R, Nolting A, Pinto P, Rajagopalan M, Ruck RT, Shah U, Soriano A, Sperbeck D, Velazquez F, Wu J, Xia Y, Venkatraman S.
Abstract : We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.
|
Inhibition of HCV genotype 1a NS3/4A protease using Ac-C(Eu)DDMEEAbu[COO]ASK(QSY7)-amide as substrate preincubated for 30 mins followed by substrate addition measured after 2.5 hrs by TRF assay
|
Hepatitis C virus subtype 1a
|
0.007
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor.
Year : 2016
Volume : 7
Issue : 1
First Page : 111
Last Page : 116
Authors : Neelamkavil SF, Agrawal S, Bara T, Bennett C, Bhat S, Biswas D, Brockunier L, Buist N, Burnette D, Cartwright M, Chackalamannil S, Chase R, Chelliah M, Chen A, Clasby M, Colandrea VJ, Davies IW, Eagen K, Guo Z, Han Y, Howe J, Jayne C, Josien H, Kargman S, Marcantonio K, Miao S, Miller R, Nolting A, Pinto P, Rajagopalan M, Ruck RT, Shah U, Soriano A, Sperbeck D, Velazquez F, Wu J, Xia Y, Venkatraman S.
Abstract : We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.
|
Antiviral activity against HCV genotype 1b infected in human HuH7 cells assessed as inhibition of viral replication after 72 hrs by RT-PCR method
|
Hepatitis C virus subtype 1b
|
0.3
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor.
Year : 2016
Volume : 7
Issue : 1
First Page : 111
Last Page : 116
Authors : Neelamkavil SF, Agrawal S, Bara T, Bennett C, Bhat S, Biswas D, Brockunier L, Buist N, Burnette D, Cartwright M, Chackalamannil S, Chase R, Chelliah M, Chen A, Clasby M, Colandrea VJ, Davies IW, Eagen K, Guo Z, Han Y, Howe J, Jayne C, Josien H, Kargman S, Marcantonio K, Miao S, Miller R, Nolting A, Pinto P, Rajagopalan M, Ruck RT, Shah U, Soriano A, Sperbeck D, Velazquez F, Wu J, Xia Y, Venkatraman S.
Abstract : We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.
|
Antiviral activity against HCV genotype 2a infected in human HuH7 cells assessed as inhibition of viral replication after 72 hrs by RT-PCR method
|
Hepatitis C virus subtype 2a
|
1.2
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor.
Year : 2016
Volume : 7
Issue : 1
First Page : 111
Last Page : 116
Authors : Neelamkavil SF, Agrawal S, Bara T, Bennett C, Bhat S, Biswas D, Brockunier L, Buist N, Burnette D, Cartwright M, Chackalamannil S, Chase R, Chelliah M, Chen A, Clasby M, Colandrea VJ, Davies IW, Eagen K, Guo Z, Han Y, Howe J, Jayne C, Josien H, Kargman S, Marcantonio K, Miao S, Miller R, Nolting A, Pinto P, Rajagopalan M, Ruck RT, Shah U, Soriano A, Sperbeck D, Velazquez F, Wu J, Xia Y, Venkatraman S.
Abstract : We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.
|
Antiviral activity against HCV genotype 2b infected in human HuH7 cells assessed as inhibition of viral replication after 72 hrs by RT-PCR method
|
Hepatitis C virus subtype 2b
|
5.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor.
Year : 2016
Volume : 7
Issue : 1
First Page : 111
Last Page : 116
Authors : Neelamkavil SF, Agrawal S, Bara T, Bennett C, Bhat S, Biswas D, Brockunier L, Buist N, Burnette D, Cartwright M, Chackalamannil S, Chase R, Chelliah M, Chen A, Clasby M, Colandrea VJ, Davies IW, Eagen K, Guo Z, Han Y, Howe J, Jayne C, Josien H, Kargman S, Marcantonio K, Miao S, Miller R, Nolting A, Pinto P, Rajagopalan M, Ruck RT, Shah U, Soriano A, Sperbeck D, Velazquez F, Wu J, Xia Y, Venkatraman S.
Abstract : We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.
|
Antiviral activity against HCV genotype 3a infected in human HuH7 cells assessed as inhibition of viral replication after 72 hrs by RT-PCR method
|
Hepatitis C virus subtype 3a
|
7.2
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor.
Year : 2016
Volume : 7
Issue : 1
First Page : 111
Last Page : 116
Authors : Neelamkavil SF, Agrawal S, Bara T, Bennett C, Bhat S, Biswas D, Brockunier L, Buist N, Burnette D, Cartwright M, Chackalamannil S, Chase R, Chelliah M, Chen A, Clasby M, Colandrea VJ, Davies IW, Eagen K, Guo Z, Han Y, Howe J, Jayne C, Josien H, Kargman S, Marcantonio K, Miao S, Miller R, Nolting A, Pinto P, Rajagopalan M, Ruck RT, Shah U, Soriano A, Sperbeck D, Velazquez F, Wu J, Xia Y, Venkatraman S.
Abstract : We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.
|
Inhibition of HCV genotype 1a NS3/4A protease assessed as substrate cleavage using Ac-C(Eu)DDMEEAbu(COO)ASK(QSY7)-amide as substrate incubated for 30 mins prior to substrate addition measured after 2.5 hrs by time-resolved fluorescence assay
|
Hepatitis C virus subtype 1a
|
0.02
nM
|
|
Journal : ACS Med Chem Lett
Title : Design and Synthesis of P2-P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors.
Year : 2016
Volume : 7
Issue : 12
First Page : 1173
Last Page : 1178
Authors : Velázquez F, Chelliah M, Clasby M, Guo Z, Howe J, Miller R, Neelamkavil S, Shah U, Soriano A, Xia Y, Venkatraman S, Chackalamannil S, Davies IW.
Abstract : A new class of hepatitis C NS3/4A inhibitors was identified by introducing a novel spirocyclic proline-P2 surrogate onto the P2-P4 macrocyclic core of MK-5172 (grazoprevir). The potency profile of new analogues showed excellent pan-genotypic activity for most compounds. The potency evaluation included the most difficult genotype 3a (EC50 values ≤10 nM) and other key genotype 1b mutants. Molecular modeling was used to design new target compounds and rationalize our results. A synthetic approach based on the Julia-Kocienski olefination and macrolactamization to assemble the P2-P4 macrocyclic core containing the novel spirocyclic proline-P2 moiety is presented as well.
|
Inhibition of HCV genotype 1b NS3/4A protease assessed as substrate cleavage using Ac-C(Eu)DDMEEAbu(COO)ASK(QSY7)-amide as substrate incubated for 30 mins prior to substrate addition measured after 2.5 hrs by time-resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
0.01
nM
|
|
Journal : ACS Med Chem Lett
Title : Design and Synthesis of P2-P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors.
Year : 2016
Volume : 7
Issue : 12
First Page : 1173
Last Page : 1178
Authors : Velázquez F, Chelliah M, Clasby M, Guo Z, Howe J, Miller R, Neelamkavil S, Shah U, Soriano A, Xia Y, Venkatraman S, Chackalamannil S, Davies IW.
Abstract : A new class of hepatitis C NS3/4A inhibitors was identified by introducing a novel spirocyclic proline-P2 surrogate onto the P2-P4 macrocyclic core of MK-5172 (grazoprevir). The potency profile of new analogues showed excellent pan-genotypic activity for most compounds. The potency evaluation included the most difficult genotype 3a (EC50 values ≤10 nM) and other key genotype 1b mutants. Molecular modeling was used to design new target compounds and rationalize our results. A synthetic approach based on the Julia-Kocienski olefination and macrolactamization to assemble the P2-P4 macrocyclic core containing the novel spirocyclic proline-P2 moiety is presented as well.
|
Inhibition of HCV genotype 2a NS3/4A protease assessed as substrate cleavage using Ac-C(Eu)DDMEEAbu(COO)ASK(QSY7)-amide as substrate incubated for 30 mins prior to substrate addition measured after 2.5 hrs by time-resolved fluorescence assay
|
Hepatitis C virus subtype 2a
|
0.14
nM
|
|
Journal : ACS Med Chem Lett
Title : Design and Synthesis of P2-P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors.
Year : 2016
Volume : 7
Issue : 12
First Page : 1173
Last Page : 1178
Authors : Velázquez F, Chelliah M, Clasby M, Guo Z, Howe J, Miller R, Neelamkavil S, Shah U, Soriano A, Xia Y, Venkatraman S, Chackalamannil S, Davies IW.
Abstract : A new class of hepatitis C NS3/4A inhibitors was identified by introducing a novel spirocyclic proline-P2 surrogate onto the P2-P4 macrocyclic core of MK-5172 (grazoprevir). The potency profile of new analogues showed excellent pan-genotypic activity for most compounds. The potency evaluation included the most difficult genotype 3a (EC50 values ≤10 nM) and other key genotype 1b mutants. Molecular modeling was used to design new target compounds and rationalize our results. A synthetic approach based on the Julia-Kocienski olefination and macrolactamization to assemble the P2-P4 macrocyclic core containing the novel spirocyclic proline-P2 moiety is presented as well.
|
Inhibition of HCV genotype 3a NS3/4A protease assessed as substrate cleavage using Ac-C(Eu)DDMEEAbu(COO)ASK(QSY7)-amide as substrate incubated for 30 mins prior to substrate addition measured after 2.5 hrs by time-resolved fluorescence assay
|
Hepatitis C virus subtype 3a
|
0.75
nM
|
|
Journal : ACS Med Chem Lett
Title : Design and Synthesis of P2-P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors.
Year : 2016
Volume : 7
Issue : 12
First Page : 1173
Last Page : 1178
Authors : Velázquez F, Chelliah M, Clasby M, Guo Z, Howe J, Miller R, Neelamkavil S, Shah U, Soriano A, Xia Y, Venkatraman S, Chackalamannil S, Davies IW.
Abstract : A new class of hepatitis C NS3/4A inhibitors was identified by introducing a novel spirocyclic proline-P2 surrogate onto the P2-P4 macrocyclic core of MK-5172 (grazoprevir). The potency profile of new analogues showed excellent pan-genotypic activity for most compounds. The potency evaluation included the most difficult genotype 3a (EC50 values ≤10 nM) and other key genotype 1b mutants. Molecular modeling was used to design new target compounds and rationalize our results. A synthetic approach based on the Julia-Kocienski olefination and macrolactamization to assemble the P2-P4 macrocyclic core containing the novel spirocyclic proline-P2 moiety is presented as well.
|
Inhibition of HCV genotype 1b NS3/4A protease R155K mutant assessed as substrate cleavage using Ac-C(Eu)DDMEEAbu(COO)ASK(QSY7)-amide as substrate incubated for 30 mins prior to substrate addition measured after 2.5 hrs by time-resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
0.06
nM
|
|
Journal : ACS Med Chem Lett
Title : Design and Synthesis of P2-P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors.
Year : 2016
Volume : 7
Issue : 12
First Page : 1173
Last Page : 1178
Authors : Velázquez F, Chelliah M, Clasby M, Guo Z, Howe J, Miller R, Neelamkavil S, Shah U, Soriano A, Xia Y, Venkatraman S, Chackalamannil S, Davies IW.
Abstract : A new class of hepatitis C NS3/4A inhibitors was identified by introducing a novel spirocyclic proline-P2 surrogate onto the P2-P4 macrocyclic core of MK-5172 (grazoprevir). The potency profile of new analogues showed excellent pan-genotypic activity for most compounds. The potency evaluation included the most difficult genotype 3a (EC50 values ≤10 nM) and other key genotype 1b mutants. Molecular modeling was used to design new target compounds and rationalize our results. A synthetic approach based on the Julia-Kocienski olefination and macrolactamization to assemble the P2-P4 macrocyclic core containing the novel spirocyclic proline-P2 moiety is presented as well.
|
Inhibition of HCV genotype 1b NS3/4A protease A156V mutant assessed as substrate cleavage using Ac-C(Eu)DDMEEAbu(COO)ASK(QSY7)-amide as substrate incubated for 30 mins prior to substrate addition measured after 2.5 hrs by time-resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
6.09
nM
|
|
Journal : ACS Med Chem Lett
Title : Design and Synthesis of P2-P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors.
Year : 2016
Volume : 7
Issue : 12
First Page : 1173
Last Page : 1178
Authors : Velázquez F, Chelliah M, Clasby M, Guo Z, Howe J, Miller R, Neelamkavil S, Shah U, Soriano A, Xia Y, Venkatraman S, Chackalamannil S, Davies IW.
Abstract : A new class of hepatitis C NS3/4A inhibitors was identified by introducing a novel spirocyclic proline-P2 surrogate onto the P2-P4 macrocyclic core of MK-5172 (grazoprevir). The potency profile of new analogues showed excellent pan-genotypic activity for most compounds. The potency evaluation included the most difficult genotype 3a (EC50 values ≤10 nM) and other key genotype 1b mutants. Molecular modeling was used to design new target compounds and rationalize our results. A synthetic approach based on the Julia-Kocienski olefination and macrolactamization to assemble the P2-P4 macrocyclic core containing the novel spirocyclic proline-P2 moiety is presented as well.
|
Inhibition of HCV genotype 1b NS3/4A protease A156T mutant assessed as substrate cleavage using Ac-C(Eu)DDMEEAbu(COO)ASK(QSY7)-amide as substrate incubated for 30 mins prior to substrate addition measured after 2.5 hrs by time-resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
3.82
nM
|
|
Journal : ACS Med Chem Lett
Title : Design and Synthesis of P2-P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors.
Year : 2016
Volume : 7
Issue : 12
First Page : 1173
Last Page : 1178
Authors : Velázquez F, Chelliah M, Clasby M, Guo Z, Howe J, Miller R, Neelamkavil S, Shah U, Soriano A, Xia Y, Venkatraman S, Chackalamannil S, Davies IW.
Abstract : A new class of hepatitis C NS3/4A inhibitors was identified by introducing a novel spirocyclic proline-P2 surrogate onto the P2-P4 macrocyclic core of MK-5172 (grazoprevir). The potency profile of new analogues showed excellent pan-genotypic activity for most compounds. The potency evaluation included the most difficult genotype 3a (EC50 values ≤10 nM) and other key genotype 1b mutants. Molecular modeling was used to design new target compounds and rationalize our results. A synthetic approach based on the Julia-Kocienski olefination and macrolactamization to assemble the P2-P4 macrocyclic core containing the novel spirocyclic proline-P2 moiety is presented as well.
|
Inhibition of HCV genotype 1b NS3/4A protease D168Y mutant assessed as substrate cleavage using Ac-C(Eu)DDMEEAbu(COO)ASK(QSY7)-amide as substrate incubated for 30 mins prior to substrate addition measured after 2.5 hrs by time-resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
0.22
nM
|
|
Journal : ACS Med Chem Lett
Title : Design and Synthesis of P2-P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors.
Year : 2016
Volume : 7
Issue : 12
First Page : 1173
Last Page : 1178
Authors : Velázquez F, Chelliah M, Clasby M, Guo Z, Howe J, Miller R, Neelamkavil S, Shah U, Soriano A, Xia Y, Venkatraman S, Chackalamannil S, Davies IW.
Abstract : A new class of hepatitis C NS3/4A inhibitors was identified by introducing a novel spirocyclic proline-P2 surrogate onto the P2-P4 macrocyclic core of MK-5172 (grazoprevir). The potency profile of new analogues showed excellent pan-genotypic activity for most compounds. The potency evaluation included the most difficult genotype 3a (EC50 values ≤10 nM) and other key genotype 1b mutants. Molecular modeling was used to design new target compounds and rationalize our results. A synthetic approach based on the Julia-Kocienski olefination and macrolactamization to assemble the P2-P4 macrocyclic core containing the novel spirocyclic proline-P2 moiety is presented as well.
|
Antiviral activity against HCV genotype 1a infected in human HuH7 cells assessed as reduction viral RNA level after 72 hrs by RT-PCR method
|
Hepatitis C virus subtype 1a
|
0.6
nM
|
|
Journal : ACS Med Chem Lett
Title : Design and Synthesis of P2-P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors.
Year : 2016
Volume : 7
Issue : 12
First Page : 1173
Last Page : 1178
Authors : Velázquez F, Chelliah M, Clasby M, Guo Z, Howe J, Miller R, Neelamkavil S, Shah U, Soriano A, Xia Y, Venkatraman S, Chackalamannil S, Davies IW.
Abstract : A new class of hepatitis C NS3/4A inhibitors was identified by introducing a novel spirocyclic proline-P2 surrogate onto the P2-P4 macrocyclic core of MK-5172 (grazoprevir). The potency profile of new analogues showed excellent pan-genotypic activity for most compounds. The potency evaluation included the most difficult genotype 3a (EC50 values ≤10 nM) and other key genotype 1b mutants. Molecular modeling was used to design new target compounds and rationalize our results. A synthetic approach based on the Julia-Kocienski olefination and macrolactamization to assemble the P2-P4 macrocyclic core containing the novel spirocyclic proline-P2 moiety is presented as well.
|
Antiviral activity against HCV genotype 1b infected in human HuH7 cells assessed as reduction viral RNA level after 72 hrs by RT-PCR method
|
Hepatitis C virus subtype 1b
|
0.6
nM
|
|
Journal : ACS Med Chem Lett
Title : Design and Synthesis of P2-P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors.
Year : 2016
Volume : 7
Issue : 12
First Page : 1173
Last Page : 1178
Authors : Velázquez F, Chelliah M, Clasby M, Guo Z, Howe J, Miller R, Neelamkavil S, Shah U, Soriano A, Xia Y, Venkatraman S, Chackalamannil S, Davies IW.
Abstract : A new class of hepatitis C NS3/4A inhibitors was identified by introducing a novel spirocyclic proline-P2 surrogate onto the P2-P4 macrocyclic core of MK-5172 (grazoprevir). The potency profile of new analogues showed excellent pan-genotypic activity for most compounds. The potency evaluation included the most difficult genotype 3a (EC50 values ≤10 nM) and other key genotype 1b mutants. Molecular modeling was used to design new target compounds and rationalize our results. A synthetic approach based on the Julia-Kocienski olefination and macrolactamization to assemble the P2-P4 macrocyclic core containing the novel spirocyclic proline-P2 moiety is presented as well.
|
Antiviral activity against HCV genotype 2a infected in human HuH7 cells assessed as reduction viral RNA level after 72 hrs by RT-PCR method
|
Hepatitis C virus subtype 2a
|
5.4
nM
|
|
Journal : ACS Med Chem Lett
Title : Design and Synthesis of P2-P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors.
Year : 2016
Volume : 7
Issue : 12
First Page : 1173
Last Page : 1178
Authors : Velázquez F, Chelliah M, Clasby M, Guo Z, Howe J, Miller R, Neelamkavil S, Shah U, Soriano A, Xia Y, Venkatraman S, Chackalamannil S, Davies IW.
Abstract : A new class of hepatitis C NS3/4A inhibitors was identified by introducing a novel spirocyclic proline-P2 surrogate onto the P2-P4 macrocyclic core of MK-5172 (grazoprevir). The potency profile of new analogues showed excellent pan-genotypic activity for most compounds. The potency evaluation included the most difficult genotype 3a (EC50 values ≤10 nM) and other key genotype 1b mutants. Molecular modeling was used to design new target compounds and rationalize our results. A synthetic approach based on the Julia-Kocienski olefination and macrolactamization to assemble the P2-P4 macrocyclic core containing the novel spirocyclic proline-P2 moiety is presented as well.
|
Antiviral activity against HCV genotype 3a infected in human HuH7 cells assessed as reduction viral RNA level after 72 hrs by RT-PCR method
|
Hepatitis C virus subtype 3a
|
7.2
nM
|
|
Journal : ACS Med Chem Lett
Title : Design and Synthesis of P2-P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors.
Year : 2016
Volume : 7
Issue : 12
First Page : 1173
Last Page : 1178
Authors : Velázquez F, Chelliah M, Clasby M, Guo Z, Howe J, Miller R, Neelamkavil S, Shah U, Soriano A, Xia Y, Venkatraman S, Chackalamannil S, Davies IW.
Abstract : A new class of hepatitis C NS3/4A inhibitors was identified by introducing a novel spirocyclic proline-P2 surrogate onto the P2-P4 macrocyclic core of MK-5172 (grazoprevir). The potency profile of new analogues showed excellent pan-genotypic activity for most compounds. The potency evaluation included the most difficult genotype 3a (EC50 values ≤10 nM) and other key genotype 1b mutants. Molecular modeling was used to design new target compounds and rationalize our results. A synthetic approach based on the Julia-Kocienski olefination and macrolactamization to assemble the P2-P4 macrocyclic core containing the novel spirocyclic proline-P2 moiety is presented as well.
|
Inhibition of HCV NS3 protease pre-incubated for 30 mins before TRF peptide substrate addition and measured after 1 hr by time resolved fluorescence assay
|
Hepatitis C virus
|
0.016
nM
|
|
Title : Macrocyclic Quinoxaline Compounds as HCV NS3 Protease Inhibitors
Year : 2010
|
Antiviral activity against Hepatitis C virus subtype 1b infected in HBI10A cells harboring HCV subgenomic bicistronic replicon assessed as reduction in viral replication
|
Hepatitis C virus subtype 1b
|
2.0
nM
|
|
Title : Macrocyclic Quinoxaline Compounds as HCV NS3 Protease Inhibitors
Year : 2010
|
Inhibition of HCV subtype 1b NS3 protease D168T mutant pre-incubated for 30 mins before TRF peptide substrate addition and measured after 1 hr by time resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
0.18
nM
|
|
Title : Macrocyclic Quinoxaline Compounds as HCV NS3 Protease Inhibitors
Year : 2010
|
Inhibition of HCV subtype 1b NS3 protease D168A mutant pre-incubated for 30 mins before TRF peptide substrate addition and measured after 1 hr by time resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
0.43
nM
|
|
Title : Macrocyclic Quinoxaline Compounds as HCV NS3 Protease Inhibitors
Year : 2010
|
Inhibition of HCV subtype 1b NS3 protease D168E mutant pre-incubated for 30 mins before TRF peptide substrate addition and measured after 1 hr by time resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
0.04
nM
|
|
Title : Macrocyclic Quinoxaline Compounds as HCV NS3 Protease Inhibitors
Year : 2010
|
Inhibition of HCV subtype 1b NS3 protease D168G mutant pre-incubated for 30 mins before TRF peptide substrate addition and measured after 1 hr by time resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
0.08
nM
|
|
Title : Macrocyclic Quinoxaline Compounds as HCV NS3 Protease Inhibitors
Year : 2010
|
Inhibition of HCV subtype 1b NS3 protease D168V mutant pre-incubated for 30 mins before TRF peptide substrate addition and measured after 1 hr by time resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
0.14
nM
|
|
Title : Macrocyclic Quinoxaline Compounds as HCV NS3 Protease Inhibitors
Year : 2010
|
Inhibition of HCV subtype 1b NS3 protease D168Y mutant pre-incubated for 30 mins before TRF peptide substrate addition and measured after 1 hr by time resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
0.22
nM
|
|
Title : Macrocyclic Quinoxaline Compounds as HCV NS3 Protease Inhibitors
Year : 2010
|
Inhibition of HCV subtype 1b NS3 protease D168Q mutant pre-incubated for 30 mins before TRF peptide substrate addition and measured after 1 hr by time resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
0.12
nM
|
|
Title : Macrocyclic Quinoxaline Compounds as HCV NS3 Protease Inhibitors
Year : 2010
|
Inhibition of HCV subtype 1b NS3 protease A156S mutant pre-incubated for 30 mins before TRF peptide substrate addition and measured after 1 hr by time resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
0.05
nM
|
|
Title : Macrocyclic Quinoxaline Compounds as HCV NS3 Protease Inhibitors
Year : 2010
|
Inhibition of HCV subtype 1b NS3 protease A156T mutant pre-incubated for 30 mins before TRF peptide substrate addition and measured after 1 hr by time resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
5.2
nM
|
|
Title : Macrocyclic Quinoxaline Compounds as HCV NS3 Protease Inhibitors
Year : 2010
|
Inhibition of HCV subtype 1b NS3 protease A156V mutant pre-incubated for 30 mins before TRF peptide substrate addition and measured after 1 hr by time resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
11.0
nM
|
|
Title : Macrocyclic Quinoxaline Compounds as HCV NS3 Protease Inhibitors
Year : 2010
|
Inhibition of HCV subtype 1b NS3 protease R155K mutant pre-incubated for 30 mins before TRF peptide substrate addition and measured after 1 hr by time resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
0.07
nM
|
|
Title : Macrocyclic Quinoxaline Compounds as HCV NS3 Protease Inhibitors
Year : 2010
|
Inhibition of HCV subtype 1b NS3 protease R155Q mutant pre-incubated for 30 mins before TRF peptide substrate addition and measured after 1 hr by time resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
0.43
nM
|
|
Title : Macrocyclic Quinoxaline Compounds as HCV NS3 Protease Inhibitors
Year : 2010
|
Inhibition of HCV subtype 1b NS3 protease R155G mutant pre-incubated for 30 mins before TRF peptide substrate addition and measured after 1 hr by time resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
0.63
nM
|
|
Title : Macrocyclic Quinoxaline Compounds as HCV NS3 Protease Inhibitors
Year : 2010
|
Inhibition of HCV subtype 1b NS3 protease R155N mutant pre-incubated for 30 mins before TRF peptide substrate addition and measured after 1 hr by time resolved fluorescence assay
|
Hepatitis C virus subtype 1b
|
0.13
nM
|
|
Title : Macrocyclic Quinoxaline Compounds as HCV NS3 Protease Inhibitors
Year : 2010
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
-4.15
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-61.53
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-57.5
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-18.42
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.0
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.09
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.08
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.09
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.0
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.08
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Inhibition of HCV NS3/4a protease using Ac-DE-Dap(QXL520)-EE-Abu-shi-[COO]AS-C(5-FAMsp)-NH2 as substrate after 15 mins
|
Hepatitis C virus
|
2.0
nM
|
|
Journal : Eur J Med Chem
Title : A review on HCV inhibitors: Significance of non-structural polyproteins.
Year : 2019
Volume : 164
First Page : 576
Last Page : 601
Authors : Ganta NM, Gedda G, Rathnakar B, Satyanarayana M, Yamajala B, Ahsan MJ, Jadav SS, Balaraju T.
Abstract : Hepatitis C virus (HCV) mortality and morbidity is a world health misery with an approximate 130-150 million chronically HCV tainted and suffering individuals and it initiate critical liver malfunction like cirrhosis, hepatocellular carcinoma or liver HCV cancer. HCV NS5B protein one of the best studied therapeutic target for the identification of new drug candidates to be added to the combination or multiple combination medication recently approved. During the past few years, NS5B has thus been an important object of attractive medicinal chemistry endeavors, which induced to the surfacing of betrothal preclinical drug molecules. In this scenario, the current review set limit to discuss research published on NS5B and few other therapeutic functional inhibitors concentrating on hit investigation, hit to lead optimization, ADME parameters evaluation, and the SAR data which was out for each compound type and similarity taken into consideration. The discussion outlined in this specific review will surly helpful and vital tool for those medicinal chemists investigators working with HCV research programs mainly pointing on NS5B and set broad spectrum identification of creative anti HCV compounds. This mini review also tells each and every individual compound ability related how much they are active against NS5B and few other targets.
|
Antiviral activity against HCV
|
Hepatitis C virus
|
9.5
nM
|
|
Journal : Eur J Med Chem
Title : A review on HCV inhibitors: Significance of non-structural polyproteins.
Year : 2019
Volume : 164
First Page : 576
Last Page : 601
Authors : Ganta NM, Gedda G, Rathnakar B, Satyanarayana M, Yamajala B, Ahsan MJ, Jadav SS, Balaraju T.
Abstract : Hepatitis C virus (HCV) mortality and morbidity is a world health misery with an approximate 130-150 million chronically HCV tainted and suffering individuals and it initiate critical liver malfunction like cirrhosis, hepatocellular carcinoma or liver HCV cancer. HCV NS5B protein one of the best studied therapeutic target for the identification of new drug candidates to be added to the combination or multiple combination medication recently approved. During the past few years, NS5B has thus been an important object of attractive medicinal chemistry endeavors, which induced to the surfacing of betrothal preclinical drug molecules. In this scenario, the current review set limit to discuss research published on NS5B and few other therapeutic functional inhibitors concentrating on hit investigation, hit to lead optimization, ADME parameters evaluation, and the SAR data which was out for each compound type and similarity taken into consideration. The discussion outlined in this specific review will surly helpful and vital tool for those medicinal chemists investigators working with HCV research programs mainly pointing on NS5B and set broad spectrum identification of creative anti HCV compounds. This mini review also tells each and every individual compound ability related how much they are active against NS5B and few other targets.
|
Inhibition of HCV NS3/4a protease
|
Hepatitis C virus
|
98.8
%
|
|
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.
|
Inhibition of HCV GT-3a NS3/4a protease using Ac-DE-D(Edans)-EE-Abu-c-[COO]-AS-K(Dabcy1)-NH2 preincubated for 1 hr followed by substrate addition
|
Hepatitis C virus subtype 3a
|
30.0
nM
|
|
|
Inhibition of HCV GT-1a NS3/4a protease using Ac-DE-D(Edans)-EE-Abu-c-[COO]-AS-K(Dabcy1)-NH2 preincubated for 1 hr followed by substrate addition
|
Hepatitis C virus subtype 3a
|
0.2
nM
|
|
|
Inhibition of HCV NS3/4a protease D168A mutant using Ac-DE-D(Edans)-EE-Abu-c-[COO]-AS-K(Dabcy1)-NH2 preincubated for 1 hr followed by substrate addition
|
Hepatitis C virus
|
49.0
nM
|
|
|
Antiviral activity against HCV genotype 1b infected in human Huh7 cells incubated for 96 hrs by luciferase assay
|
Hepatitis C virus
|
0.2
nM
|
|
|
Antiviral activity against HCV genotype 1b harboring A156T mutant infected in human Huh7 cells incubated for 96 hrs by luciferase assay
|
Hepatitis C virus
|
261.0
nM
|
|
|
Antiviral activity against HCV genotype 1b harboring D168A mutant infected in human Huh7 cells incubated for 96 hrs by luciferase assay
|
Hepatitis C virus
|
12.0
nM
|
|
|
Antiviral activity against HCV genotype 3a infected in human Huh7.5 cells incubated for 72 hrs by luciferase assay
|
Hepatitis C virus
|
65.0
nM
|
|
