|
Inhibition of HCV1b BK full length NS3/4A protease expressed in Escherichia coli after 1 hr by time-resolved fluorescence assay
|
Hepatitis C virus (isolate BK)
|
0.05
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor.
Year : 2010
Volume : 53
Issue : 6
First Page : 2443
Last Page : 2463
Authors : McCauley JA, McIntyre CJ, Rudd MT, Nguyen KT, Romano JJ, Butcher JW, Gilbert KF, Bush KJ, Holloway MK, Swestock J, Wan BL, Carroll SS, DiMuzio JM, Graham DJ, Ludmerer SW, Mao SS, Stahlhut MW, Fandozzi CM, Trainor N, Olsen DB, Vacca JP, Liverton NJ.
Abstract : A new class of HCV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the P1 side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.
|
Inhibition of HCV JFH-1 full length NS3/4A protease expressed in Escherichia coli after 1 hr by time-resolved fluorescence assay
|
Hepatitis C virus JFH-1
|
0.9
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor.
Year : 2010
Volume : 53
Issue : 6
First Page : 2443
Last Page : 2463
Authors : McCauley JA, McIntyre CJ, Rudd MT, Nguyen KT, Romano JJ, Butcher JW, Gilbert KF, Bush KJ, Holloway MK, Swestock J, Wan BL, Carroll SS, DiMuzio JM, Graham DJ, Ludmerer SW, Mao SS, Stahlhut MW, Fandozzi CM, Trainor N, Olsen DB, Vacca JP, Liverton NJ.
Abstract : A new class of HCV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the P1 side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.
|
Antiviral activity against HCV Con1 infected in human HuH7 cells assessed as inhibition of viral replication after 24 hrs by replicon assay in presence of 10% fetal bovine serum
|
Hepatitis C virus
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor.
Year : 2010
Volume : 53
Issue : 6
First Page : 2443
Last Page : 2463
Authors : McCauley JA, McIntyre CJ, Rudd MT, Nguyen KT, Romano JJ, Butcher JW, Gilbert KF, Bush KJ, Holloway MK, Swestock J, Wan BL, Carroll SS, DiMuzio JM, Graham DJ, Ludmerer SW, Mao SS, Stahlhut MW, Fandozzi CM, Trainor N, Olsen DB, Vacca JP, Liverton NJ.
Abstract : A new class of HCV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the P1 side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.
|
Antiviral activity against HCV Con1 infected in human HuH7 cells assessed as inhibition of viral replication after 24 hrs by replicon assay in presence of 50% normal human serum
|
Hepatitis C virus
|
19.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor.
Year : 2010
Volume : 53
Issue : 6
First Page : 2443
Last Page : 2463
Authors : McCauley JA, McIntyre CJ, Rudd MT, Nguyen KT, Romano JJ, Butcher JW, Gilbert KF, Bush KJ, Holloway MK, Swestock J, Wan BL, Carroll SS, DiMuzio JM, Graham DJ, Ludmerer SW, Mao SS, Stahlhut MW, Fandozzi CM, Trainor N, Olsen DB, Vacca JP, Liverton NJ.
Abstract : A new class of HCV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the P1 side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.
|
Antiviral activity against HCV JFH-1 infected in human HuH7 cells assessed as inhibition of viral replication after 24 hrs by replicon assay in presence of 10% fetal bovine serum
|
Hepatitis C virus JFH-1
|
9.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor.
Year : 2010
Volume : 53
Issue : 6
First Page : 2443
Last Page : 2463
Authors : McCauley JA, McIntyre CJ, Rudd MT, Nguyen KT, Romano JJ, Butcher JW, Gilbert KF, Bush KJ, Holloway MK, Swestock J, Wan BL, Carroll SS, DiMuzio JM, Graham DJ, Ludmerer SW, Mao SS, Stahlhut MW, Fandozzi CM, Trainor N, Olsen DB, Vacca JP, Liverton NJ.
Abstract : A new class of HCV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the P1 side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.
|
Inhibition of HCV NS3 protease by FRET assay
|
Hepatitis C virus
|
0.06
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Improved P2 phenylglycine-based hepatitis C virus NS3 protease inhibitors with alkenylic prime-side substituents.
Year : 2010
Volume : 18
Issue : 14
First Page : 5413
Last Page : 5424
Authors : Lampa A, Ehrenberg AE, Gustafsson SS, Vema A, Kerblom E, Lindeberg G, Karlén A, Danielson UH, Sandström A.
Abstract : Phenylglycine has proved to be a useful P2 residue in HCV NS3 protease inhibitors. A novel pi-pi-interaction between the phenylglycine and the catalytic H57 residue of the protease is postulated. We hypothesized that the introduction of a vinyl on the phenylglycine might strengthen this pi-pi-interaction. Thus, herein is presented the synthesis and inhibitory potency of a series of acyclic vinylated phenylglycine-based HCV NS3 protease inhibitors. Surprisingly, inhibitors based on both D- and L-phenylglycine were found to be effective inhibitors, with a slight preference for the d-epimers. Furthermore, prime-side alkenylic extension of the C-terminal acylsulfonamide group gave significantly improved inhibitors with potencies in the nanomolar range (approximately 35 nM), potencies which were retained on mutant variants of the protease.
|
Antiviral activity against HCV 1B infected in human Huh7 cells by firefly luciferase reporter gene assay
|
Hepatitis C virus subtype 1b
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Improved P2 phenylglycine-based hepatitis C virus NS3 protease inhibitors with alkenylic prime-side substituents.
Year : 2010
Volume : 18
Issue : 14
First Page : 5413
Last Page : 5424
Authors : Lampa A, Ehrenberg AE, Gustafsson SS, Vema A, Kerblom E, Lindeberg G, Karlén A, Danielson UH, Sandström A.
Abstract : Phenylglycine has proved to be a useful P2 residue in HCV NS3 protease inhibitors. A novel pi-pi-interaction between the phenylglycine and the catalytic H57 residue of the protease is postulated. We hypothesized that the introduction of a vinyl on the phenylglycine might strengthen this pi-pi-interaction. Thus, herein is presented the synthesis and inhibitory potency of a series of acyclic vinylated phenylglycine-based HCV NS3 protease inhibitors. Surprisingly, inhibitors based on both D- and L-phenylglycine were found to be effective inhibitors, with a slight preference for the d-epimers. Furthermore, prime-side alkenylic extension of the C-terminal acylsulfonamide group gave significantly improved inhibitors with potencies in the nanomolar range (approximately 35 nM), potencies which were retained on mutant variants of the protease.
|
Antiviral activity against Hepatitis C virus containing NS3/4a Con1 sequence by transient cell-base protease activity
|
Hepatitis C virus
|
4.1
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Antiviral activity against Hepatitis C virus containing NS3/4a H77 sequence by transient cell-base protease activity
|
Hepatitis C virus
|
4.5
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Antiviral activity against Hepatitis C virus containing NS3/4a ps20 sequence by transient cell-base protease activity
|
Hepatitis C virus
|
2.9
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Antiviral activity against Hepatitis C virus containing NS3/4a ps30 sequence by transient cell-base protease activity
|
Hepatitis C virus
|
27.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Antiviral activity against Hepatitis C virus containing NS3/4a ps31 sequence by transient cell-base protease activity
|
Hepatitis C virus
|
3.4
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Antiviral activity against Hepatitis C virus containing NS3/4a ps32 sequence by transient cell-base protease activity
|
Hepatitis C virus
|
3.8
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Antiviral activity against Hepatitis C virus containing NS3/4a ps33 sequence by transient cell-base protease activity
|
Hepatitis C virus
|
9.5
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Inhibition of human Chymotrypsin
|
Homo sapiens
|
520.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Antiviral activity against Hepatitis C virus containing NS3/D168Y protease mutant activity by TaqMan-based assay
|
Hepatitis C virus
|
430.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Antiviral activity against Hepatitis C virus containing NS3/A156T protease mutant activity by TaqMan-based assay
|
Hepatitis C virus
|
200.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Antiviral activity against Hepatitis C virus containing NS3/R155K protease mutant activity by TaqMan-based assay
|
Hepatitis C virus
|
350.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Antiviral activity against Hepatitis C virus containing NS3/F43S protease mutant activity by TaqMan-based assay
|
Hepatitis C virus
|
7.8
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Antiviral activity against Hepatitis C virus containing NS3/Q41R protease mutant activity by TaqMan-based assay
|
Hepatitis C virus
|
5.2
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Antiviral activity against Hepatitis C virus genotype 1a containing NS3/con1 protease mutant by TaqMan-based assay
|
Hepatitis C virus subtype 1a
|
1.6
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Antiviral activity against Hepatitis C virus genotype 2a infected in mouse HB1 cell by cell-based HCV replicon assay in presence of 10% fetal bovine serum
|
Hepatitis C virus subtype 2a
|
15.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Antiviral activity against Hepatitis C virus genotype 1b infected in mouse HB1 cell by cell-based HCV replicon assay in presence of 50% normal human serum
|
Hepatitis C virus subtype 1b
|
13.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Antiviral activity against Hepatitis C virus genotype 1b infected in mouse HB1 cell by cell-based HCV replicon assay in presence of 10% fetal bovine serum
|
Hepatitis C virus subtype 1b
|
5.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Inhibition of Hepatitis C virus genotype 2b NS3/4A protease activity
|
Hepatitis C virus subtype 2b
|
1.4
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Inhibition of Hepatitis C virus genotype 2a NS3/4A protease activity
|
Hepatitis C virus subtype 2a
|
1.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Inhibition of Hepatitis C virus genotype 1b NS3/4A protease activity
|
Hepatitis C virus subtype 1b
|
0.06
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Inhibition of Hepatitis C virus genotype 1a NS3/4A protease activity
|
Hepatitis C virus subtype 1a
|
0.07
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Antiviral activity against Hepatitis C virus containing NS3/4a ps36 sequence by transient cell-base protease activity
|
Hepatitis C virus
|
4.9
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Antiviral activity against Hepatitis C virus containing NS3/4a ps37 sequence by transient cell-base protease activity
|
Hepatitis C virus
|
6.5
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Antiviral activity against Hepatitis C virus containing NS3/4a ps38 sequence by transient cell-base protease activity
|
Hepatitis C virus
|
6.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Antiviral activity against Hepatitis C virus containing NS3/4a ps40 sequence by transient cell-base protease activity
|
Hepatitis C virus
|
2.9
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Antiviral activity against Hepatitis C virus containing NS3/4a ps41 sequence by transient cell-base protease activity
|
Hepatitis C virus
|
19.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Antiviral activity against HCV 1a infected in human hepatoma cells by replicon assay
|
Hepatitis C virus subtype 1a
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel macrocyclic HCV NS3 protease inhibitors derived from α-amino cyclic boronates.
Year : 2010
Volume : 20
Issue : 19
First Page : 5695
Last Page : 5700
Authors : Li X, Zhang YK, Liu Y, Ding CZ, Zhou Y, Li Q, Plattner JJ, Baker SJ, Zhang S, Kazmierski WM, Wright LL, Smith GK, Grimes RM, Crosby RM, Creech KL, Carballo LH, Slater MJ, Jarvest RL, Thommes P, Hubbard JA, Convery MA, Nassau PM, McDowell W, Skarzynski TJ, Qian X, Fan D, Liao L, Ni ZJ, Pennicott LE, Zou W, Wright J.
Abstract : A novel series of P2-P4 macrocyclic HCV NS3/4A protease inhibitors with α-amino cyclic boronates as warheads at the P1 site was designed and synthesized. When compared to their linear analogs, these macrocyclic inhibitors exhibited a remarkable improvement in cell-based replicon activities, with compounds 9a and 9e reaching sub-micromolar potency in replicon assay. The SAR around α-amino cyclic boronates clearly established the influence of ring size, chirality and of the substitution pattern. Furthermore, X-ray structure of the co-crystal of inhibitor 9a and NS3 protease revealed that Ser-139 in the enzyme active site traps boron in the warhead region of 9a, thus establishing its mode of action.
|
Antiviral activity against HCV 1b infected in human hepatoma cells by replicon assay
|
Hepatitis C virus subtype 1b
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel macrocyclic HCV NS3 protease inhibitors derived from α-amino cyclic boronates.
Year : 2010
Volume : 20
Issue : 19
First Page : 5695
Last Page : 5700
Authors : Li X, Zhang YK, Liu Y, Ding CZ, Zhou Y, Li Q, Plattner JJ, Baker SJ, Zhang S, Kazmierski WM, Wright LL, Smith GK, Grimes RM, Crosby RM, Creech KL, Carballo LH, Slater MJ, Jarvest RL, Thommes P, Hubbard JA, Convery MA, Nassau PM, McDowell W, Skarzynski TJ, Qian X, Fan D, Liao L, Ni ZJ, Pennicott LE, Zou W, Wright J.
Abstract : A novel series of P2-P4 macrocyclic HCV NS3/4A protease inhibitors with α-amino cyclic boronates as warheads at the P1 site was designed and synthesized. When compared to their linear analogs, these macrocyclic inhibitors exhibited a remarkable improvement in cell-based replicon activities, with compounds 9a and 9e reaching sub-micromolar potency in replicon assay. The SAR around α-amino cyclic boronates clearly established the influence of ring size, chirality and of the substitution pattern. Furthermore, X-ray structure of the co-crystal of inhibitor 9a and NS3 protease revealed that Ser-139 in the enzyme active site traps boron in the warhead region of 9a, thus establishing its mode of action.
|
Antiviral activity against HCV1b Con1 harboring NS3 protease gene infected in human Huh7/Lunet cells assessed as inhibition of viral replication after 3 days by luciferase based transient-transfection assay
|
Hepatitis C virus
|
0.7
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Susceptibility of treatment-naive hepatitis C virus (HCV) clinical isolates to HCV protease inhibitors.
Year : 2010
Volume : 54
Issue : 12
First Page : 5288
Last Page : 5297
Authors : Bae A, Sun SC, Qi X, Chen X, Ku K, Worth A, Wong KA, Harris J, Miller MD, Mo H.
Abstract : In order to assess the natural variation in susceptibility to hepatitis C virus (HCV) NS3 protease inhibitors (PIs) among untreated HCV patient samples, the susceptibilities of 39 baseline clinical isolates were determined using a transient-replication assay on a panel of HCV PIs, including two α-ketoamides (VX-950 and SCH-503034) and three macrocyclic inhibitors (MK-7009, ITMN-191, and TMC-435350). Some natural variation in susceptibility to all HCV PIs tested was observed among the baseline clinical isolates. The susceptibility to VX-950 correlated strongly with the susceptibility to SCH-503034. A moderate correlation was observed between the susceptibilities to ITMN-191 and MK-7009. In contrast, the phenotypic correlations between the α-ketoamides and macrocyclic inhibitors were significantly lower. This difference is partly attributable to reduced susceptibility of the HCV variants containing the NS3 polymorphism Q80K (existing in 47% of genotype 1a isolates) to the macrocyclic compounds but no change in the sensitivity of the same variants to the α-ketoamides tested. Our results suggest that the natural variation in baseline susceptibility may contribute to different degrees of antiviral response among patients in vivo, particularly at lower doses.
|
Antiviral activity against HCV1b harboring Q80Q polymorphism in NS3 protease gene infected in human Huh7/Lunet cells assessed as inhibition of viral replication after 3 days by luciferase based transient-transfection assay
|
Hepatitis C virus subtype 1b
|
0.27
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Susceptibility of treatment-naive hepatitis C virus (HCV) clinical isolates to HCV protease inhibitors.
Year : 2010
Volume : 54
Issue : 12
First Page : 5288
Last Page : 5297
Authors : Bae A, Sun SC, Qi X, Chen X, Ku K, Worth A, Wong KA, Harris J, Miller MD, Mo H.
Abstract : In order to assess the natural variation in susceptibility to hepatitis C virus (HCV) NS3 protease inhibitors (PIs) among untreated HCV patient samples, the susceptibilities of 39 baseline clinical isolates were determined using a transient-replication assay on a panel of HCV PIs, including two α-ketoamides (VX-950 and SCH-503034) and three macrocyclic inhibitors (MK-7009, ITMN-191, and TMC-435350). Some natural variation in susceptibility to all HCV PIs tested was observed among the baseline clinical isolates. The susceptibility to VX-950 correlated strongly with the susceptibility to SCH-503034. A moderate correlation was observed between the susceptibilities to ITMN-191 and MK-7009. In contrast, the phenotypic correlations between the α-ketoamides and macrocyclic inhibitors were significantly lower. This difference is partly attributable to reduced susceptibility of the HCV variants containing the NS3 polymorphism Q80K (existing in 47% of genotype 1a isolates) to the macrocyclic compounds but no change in the sensitivity of the same variants to the α-ketoamides tested. Our results suggest that the natural variation in baseline susceptibility may contribute to different degrees of antiviral response among patients in vivo, particularly at lower doses.
|
Antiviral activity against HCV1b harboring Q80K polymorphism in NS3 protease gene infected in human Huh7/Lunet cells assessed as inhibition of viral replication after 3 days by luciferase based transient-transfection assay
|
Hepatitis C virus subtype 1b
|
0.41
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Susceptibility of treatment-naive hepatitis C virus (HCV) clinical isolates to HCV protease inhibitors.
Year : 2010
Volume : 54
Issue : 12
First Page : 5288
Last Page : 5297
Authors : Bae A, Sun SC, Qi X, Chen X, Ku K, Worth A, Wong KA, Harris J, Miller MD, Mo H.
Abstract : In order to assess the natural variation in susceptibility to hepatitis C virus (HCV) NS3 protease inhibitors (PIs) among untreated HCV patient samples, the susceptibilities of 39 baseline clinical isolates were determined using a transient-replication assay on a panel of HCV PIs, including two α-ketoamides (VX-950 and SCH-503034) and three macrocyclic inhibitors (MK-7009, ITMN-191, and TMC-435350). Some natural variation in susceptibility to all HCV PIs tested was observed among the baseline clinical isolates. The susceptibility to VX-950 correlated strongly with the susceptibility to SCH-503034. A moderate correlation was observed between the susceptibilities to ITMN-191 and MK-7009. In contrast, the phenotypic correlations between the α-ketoamides and macrocyclic inhibitors were significantly lower. This difference is partly attributable to reduced susceptibility of the HCV variants containing the NS3 polymorphism Q80K (existing in 47% of genotype 1a isolates) to the macrocyclic compounds but no change in the sensitivity of the same variants to the α-ketoamides tested. Our results suggest that the natural variation in baseline susceptibility may contribute to different degrees of antiviral response among patients in vivo, particularly at lower doses.
|
Antiviral activity against Hepatitis C virus subtype 1b harboring protease A156T mutant by transient replicon assay
|
Hepatitis C virus subtype 1b
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
Year : 2012
Volume : 55
Issue : 7
First Page : 3021
Last Page : 3026
Authors : Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
Abstract : The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
|
Antiviral activity against wild type Hepatitis C virus subtype 1b by transient replicon assay
|
Hepatitis C virus subtype 1b
|
1.6
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
Year : 2012
Volume : 55
Issue : 7
First Page : 3021
Last Page : 3026
Authors : Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
Abstract : The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
|
Antiviral activity against Hepatitis C virus subtype 1b harboring protease R155K mutant by transient replicon assay
|
Hepatitis C virus subtype 1b
|
350.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
Year : 2012
Volume : 55
Issue : 7
First Page : 3021
Last Page : 3026
Authors : Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
Abstract : The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
|
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)
|
0.05
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)
|
54.0
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 R155K mutant expressed in Escherichia coli by time-resolved fluorescence analysis
|
Hepatitis C virus (isolate BK)
|
19.0
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 A156T mutant expressed in Escherichia coli by time-resolved fluorescence analysis
|
Hepatitis C virus (isolate BK)
|
22.0
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 A156V mutant expressed in Escherichia coli by time-resolved fluorescence analysis
|
Hepatitis C virus (isolate BK)
|
88.0
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)
|
77.0
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.
|
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)
|
19.0
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 HCV3a NS3/4A protease
|
Hepatitis C virus subtype 3a
|
54.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Development of potent macrocyclic inhibitors of genotype 3a HCV NS3/4A protease.
Year : 2012
Volume : 22
Issue : 23
First Page : 7201
Last Page : 7206
Authors : Rudd MT, McCauley JA, Romano JJ, Butcher JW, Bush K, McIntyre CJ, Nguyen KT, Gilbert KF, Lyle TA, Holloway MK, Wan BL, Vacca JP, Summa V, Harper S, Rowley M, Carroll SS, Burlein C, DiMuzio JM, Gates A, Graham DJ, Huang Q, Ludmerer SW, McClain S, McHale C, Stahlhut M, Fandozzi C, Taylor A, Trainor N, Olsen DB, Liverton NJ.
Abstract : A series of macrocyclic compounds containing 2-substituted-quinoline moieties have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K mutant activity while maintaining the high rat liver exposure. Cyclization of the 2-substituted quinoline substituent led to a series of tricyclic P2 compounds which also display superb gt3a potency.
|
Inhibition of Hepatitis C virus genotype 1b NS3/4A protease V170A mutant
|
Hepatitis C virus subtype 1b
|
4.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Azetidines and spiro azetidines as novel P2 units in hepatitis C virus NS3 protease inhibitors.
Year : 2013
Volume : 23
Issue : 23
First Page : 6325
Last Page : 6330
Authors : Bondada L, Rondla R, Pradere U, Liu P, Li C, Bobeck D, McBrayer T, Tharnish P, Courcambeck J, Halfon P, Whitaker T, Amblard F, Coats SJ, Schinazi RF.
Abstract : Herein, we report the synthesis and structure-activity relationship studies of new analogs of boceprevir 1 and telaprevir 2. Introduction of azetidine and spiroazetidines as a P2 substituent that replaced the pyrrolidine moiety of 1 and 2 led to the discovery of a potent hepatitis C protease inhibitor 37c (EC50=0.8 μM).
|
Inhibition of Hepatitis C virus genotype 1b NS3/4A protease A156S mutant
|
Hepatitis C virus subtype 1b
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Azetidines and spiro azetidines as novel P2 units in hepatitis C virus NS3 protease inhibitors.
Year : 2013
Volume : 23
Issue : 23
First Page : 6325
Last Page : 6330
Authors : Bondada L, Rondla R, Pradere U, Liu P, Li C, Bobeck D, McBrayer T, Tharnish P, Courcambeck J, Halfon P, Whitaker T, Amblard F, Coats SJ, Schinazi RF.
Abstract : Herein, we report the synthesis and structure-activity relationship studies of new analogs of boceprevir 1 and telaprevir 2. Introduction of azetidine and spiroazetidines as a P2 substituent that replaced the pyrrolidine moiety of 1 and 2 led to the discovery of a potent hepatitis C protease inhibitor 37c (EC50=0.8 μM).
|
Inhibition of Hepatitis C virus genotype 1b NS3/4A protease V36M mutant
|
Hepatitis C virus subtype 1b
|
45.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Azetidines and spiro azetidines as novel P2 units in hepatitis C virus NS3 protease inhibitors.
Year : 2013
Volume : 23
Issue : 23
First Page : 6325
Last Page : 6330
Authors : Bondada L, Rondla R, Pradere U, Liu P, Li C, Bobeck D, McBrayer T, Tharnish P, Courcambeck J, Halfon P, Whitaker T, Amblard F, Coats SJ, Schinazi RF.
Abstract : Herein, we report the synthesis and structure-activity relationship studies of new analogs of boceprevir 1 and telaprevir 2. Introduction of azetidine and spiroazetidines as a P2 substituent that replaced the pyrrolidine moiety of 1 and 2 led to the discovery of a potent hepatitis C protease inhibitor 37c (EC50=0.8 μM).
|
Inhibition of Hepatitis C virus genotype 1b NS3/4A protease A156T mutant
|
Hepatitis C virus subtype 1b
|
910.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Azetidines and spiro azetidines as novel P2 units in hepatitis C virus NS3 protease inhibitors.
Year : 2013
Volume : 23
Issue : 23
First Page : 6325
Last Page : 6330
Authors : Bondada L, Rondla R, Pradere U, Liu P, Li C, Bobeck D, McBrayer T, Tharnish P, Courcambeck J, Halfon P, Whitaker T, Amblard F, Coats SJ, Schinazi RF.
Abstract : Herein, we report the synthesis and structure-activity relationship studies of new analogs of boceprevir 1 and telaprevir 2. Introduction of azetidine and spiroazetidines as a P2 substituent that replaced the pyrrolidine moiety of 1 and 2 led to the discovery of a potent hepatitis C protease inhibitor 37c (EC50=0.8 μM).
|
Inhibition of Hepatitis C virus genotype 1b wild type NS3/4A protease
|
Hepatitis C virus subtype 1b
|
6.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Azetidines and spiro azetidines as novel P2 units in hepatitis C virus NS3 protease inhibitors.
Year : 2013
Volume : 23
Issue : 23
First Page : 6325
Last Page : 6330
Authors : Bondada L, Rondla R, Pradere U, Liu P, Li C, Bobeck D, McBrayer T, Tharnish P, Courcambeck J, Halfon P, Whitaker T, Amblard F, Coats SJ, Schinazi RF.
Abstract : Herein, we report the synthesis and structure-activity relationship studies of new analogs of boceprevir 1 and telaprevir 2. Introduction of azetidine and spiroazetidines as a P2 substituent that replaced the pyrrolidine moiety of 1 and 2 led to the discovery of a potent hepatitis C protease inhibitor 37c (EC50=0.8 μM).
|
Inhibition of HCV genotype 1a NS3/4A protease using Ac-DED(Edans)EEAbu-psi[COO]ASK(Dabcyl)-NH2 as substrate by FRET assay
|
Hepatitis C virus subtype 1a
|
0.05
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles.
Year : 2014
Volume : 22
Issue : 23
First Page : 6595
Last Page : 6615
Authors : Lampa A, Alogheli H, Ehrenberg AE, Åkerblom E, Svensson R, Artursson P, Danielson UH, Karlén A, Sandström A.
Abstract : With three recent market approvals and several inhibitors in advanced stages of development, the hepatitis C virus (HCV) NS3/4A protease represents a successful target for antiviral therapy against hepatitis C. As a consequence of dealing with viral diseases in general, there are concerns related to the emergence of drug resistant strains which calls for development of inhibitors with an alternative binding-mode than the existing highly optimized ones. We have previously reported on the use of phenylglycine as an alternative P2 residue in HCV NS3/4A protease inhibitors. Herein, we present the synthesis, structure-activity relationships and in vitro pharmacokinetic characterization of a diverse series of linear and macrocyclic P2 pyrimidinyloxyphenylglycine based inhibitors. With access to vinyl substituents in P3, P2 and P1' positions an initial probing of macrocyclization between different positions, using ring-closing metathesis (RCM) could be performed, after addressing some synthetic challenges. Biochemical results from the wild type enzyme and drug resistant variants (e.g., R155 K) indicate that P3-P1' macrocyclization, leaving the P2 substituent in a flexible mode, is a promising approach. Additionally, the study demonstrates that phenylglycine based inhibitors benefit from p-phenylpyrimidinyloxy and m-vinyl groups as well as from the combination with an aromatic P1 motif with alkenylic P1' elongations. In fact, linear P2-P1' spanning intermediate compounds based on these fragments were found to display promising inhibitory potencies and drug like properties.
|
Antiviral activity against HCV genotype 1a
|
Hepatitis C virus subtype 1a
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles.
Year : 2014
Volume : 22
Issue : 23
First Page : 6595
Last Page : 6615
Authors : Lampa A, Alogheli H, Ehrenberg AE, Åkerblom E, Svensson R, Artursson P, Danielson UH, Karlén A, Sandström A.
Abstract : With three recent market approvals and several inhibitors in advanced stages of development, the hepatitis C virus (HCV) NS3/4A protease represents a successful target for antiviral therapy against hepatitis C. As a consequence of dealing with viral diseases in general, there are concerns related to the emergence of drug resistant strains which calls for development of inhibitors with an alternative binding-mode than the existing highly optimized ones. We have previously reported on the use of phenylglycine as an alternative P2 residue in HCV NS3/4A protease inhibitors. Herein, we present the synthesis, structure-activity relationships and in vitro pharmacokinetic characterization of a diverse series of linear and macrocyclic P2 pyrimidinyloxyphenylglycine based inhibitors. With access to vinyl substituents in P3, P2 and P1' positions an initial probing of macrocyclization between different positions, using ring-closing metathesis (RCM) could be performed, after addressing some synthetic challenges. Biochemical results from the wild type enzyme and drug resistant variants (e.g., R155 K) indicate that P3-P1' macrocyclization, leaving the P2 substituent in a flexible mode, is a promising approach. Additionally, the study demonstrates that phenylglycine based inhibitors benefit from p-phenylpyrimidinyloxy and m-vinyl groups as well as from the combination with an aromatic P1 motif with alkenylic P1' elongations. In fact, linear P2-P1' spanning intermediate compounds based on these fragments were found to display promising inhibitory potencies and drug like properties.
|
Antiviral activity against HCV
|
Hepatitis C virus
|
3.0
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.
