|
Binding affinity at HCV NS3 protease
|
Hepatitis C virus subtype 1b
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]- 3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (SCH 503034), a selective, potent, orally bioavailable hepatitis C virus NS3 protease inhibitor: a potential therapeutic agent for the treatment of hepatitis C infection.
Year : 2006
Volume : 49
Issue : 20
First Page : 6074
Last Page : 6086
Authors : Venkatraman S, Bogen SL, Arasappan A, Bennett F, Chen K, Jao E, Liu YT, Lovey R, Hendrata S, Huang Y, Pan W, Parekh T, Pinto P, Popov V, Pike R, Ruan S, Santhanam B, Vibulbhan B, Wu W, Yang W, Kong J, Liang X, Wong J, Liu R, Butkiewicz N, Chase R, Hart A, Agrawal S, Ingravallo P, Pichardo J, Kong R, Baroudy B, Malcolm B, Guo Z, Prongay A, Madison V, Broske L, Cui X, Cheng KC, Hsieh Y, Brisson JM, Prelusky D, Korfmacher W, White R, Bogdanowich-Knipp S, Pavlovsky A, Bradley P, Saksena AK, Ganguly A, Piwinski J, Girijavallabhan V, Njoroge FG.
Abstract : Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 170 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-alpha or polyethylene glycol (PEG)-interferon-alpha alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of 70 (SCH 503034), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been advanced to clinical trials in human beings for the treatment of hepatitis C viral infections is described. X-ray structure of inhibitor 70 complexed with the NS3 protease and biological data are also discussed.
|
Inhibition of hepatitis C virus NS3 serine protease
|
Hepatitis C virus
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Potent and selective small molecule NS3 serine protease inhibitors of Hepatitis C virus with dichlorocyclopropylproline as P2 residue.
Year : 2008
Volume : 16
Issue : 4
First Page : 1874
Last Page : 1883
Authors : Chen KX, Vibulbhan B, Yang W, Cheng KC, Liu R, Pichardo J, Butkiewicz N, Njoroge FG.
Abstract : Starting from a pentapeptide Hepatitis C virus NS3 protease inhibitor, a number of alpha-ketoamide inhibitors based on novel dichlorocyclopropylproline P2 core were synthesized and investigated for their HCV NS3 serine protease activity. The key intermediate 3,4-dichlorocyclopropylproline was obtained through a dichloro carbene insertion to 3,4-dehydroproline. The size of the molecules was reduced significantly through a series of truncations of the initial pentapeptide. By varying P1 side chain in length and size, potency and selectivity were improved. A variety of aliphatic carbamate and urea capping groups were examined. In general, compounds with urea cappings were more potent and selective than their carbamate counterparts. The most potent compound was a tert-butyl urea analog. Variations at P3 position were also investigated. Among the three residues incorporated, tert-leucine was clearly superior, leading to compounds that had excellent enzyme potency and selectivity. The most potent compound achieved cell-based replicon assay EC50 of 40 nM. The most promising compound of all had excellent potency in both enzyme (Ki* = 9 nM) and replicon assays (EC50 = 100 nM). Its bioavailabilities were above 10% in all three animal species (rats, monkeys, and dogs). It has provided a lead for future investigations.
|
Antiviral activity in hepatitis C virus by cell based replicon assay
|
Hepatitis C virus
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Potent and selective small molecule NS3 serine protease inhibitors of Hepatitis C virus with dichlorocyclopropylproline as P2 residue.
Year : 2008
Volume : 16
Issue : 4
First Page : 1874
Last Page : 1883
Authors : Chen KX, Vibulbhan B, Yang W, Cheng KC, Liu R, Pichardo J, Butkiewicz N, Njoroge FG.
Abstract : Starting from a pentapeptide Hepatitis C virus NS3 protease inhibitor, a number of alpha-ketoamide inhibitors based on novel dichlorocyclopropylproline P2 core were synthesized and investigated for their HCV NS3 serine protease activity. The key intermediate 3,4-dichlorocyclopropylproline was obtained through a dichloro carbene insertion to 3,4-dehydroproline. The size of the molecules was reduced significantly through a series of truncations of the initial pentapeptide. By varying P1 side chain in length and size, potency and selectivity were improved. A variety of aliphatic carbamate and urea capping groups were examined. In general, compounds with urea cappings were more potent and selective than their carbamate counterparts. The most potent compound was a tert-butyl urea analog. Variations at P3 position were also investigated. Among the three residues incorporated, tert-leucine was clearly superior, leading to compounds that had excellent enzyme potency and selectivity. The most potent compound achieved cell-based replicon assay EC50 of 40 nM. The most promising compound of all had excellent potency in both enzyme (Ki* = 9 nM) and replicon assays (EC50 = 100 nM). Its bioavailabilities were above 10% in all three animal species (rats, monkeys, and dogs). It has provided a lead for future investigations.
|
Inhibition of HCV NS3 protease by FRET assay
|
Hepatitis C virus
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Hepatitis C virus NS3 protease inhibitors comprising a novel aromatic P1 moiety.
Year : 2008
Volume : 16
Issue : 6
First Page : 2955
Last Page : 2967
Authors : Rönn R, Lampa A, Peterson SD, Gossas T, Akerblom E, Danielson UH, Karlén A, Sandström A.
Abstract : Inhibition of the hepatitis C virus (HCV) NS3 protease has emerged as an attractive approach to defeat the global hepatitis C epidemic. In this work, we present the synthesis and biochemical evaluation of HCV NS3 protease inhibitors comprising a non-natural aromatic P(1) moiety. A series of inhibitors with aminobenzoyl sulfonamides displaying submicromolar potencies in the full-length NS3 protease assay was prepared through a microwave-irradiated, palladium-catalyzed, amidocarbonylation protocol.
|
Antiviral activity against Hepatitis C virus infected human hepatoma cells by replicon assay
|
Hepatitis C virus
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Hepatitis C virus NS3 protease inhibitors comprising a novel aromatic P1 moiety.
Year : 2008
Volume : 16
Issue : 6
First Page : 2955
Last Page : 2967
Authors : Rönn R, Lampa A, Peterson SD, Gossas T, Akerblom E, Danielson UH, Karlén A, Sandström A.
Abstract : Inhibition of the hepatitis C virus (HCV) NS3 protease has emerged as an attractive approach to defeat the global hepatitis C epidemic. In this work, we present the synthesis and biochemical evaluation of HCV NS3 protease inhibitors comprising a non-natural aromatic P(1) moiety. A series of inhibitors with aminobenzoyl sulfonamides displaying submicromolar potencies in the full-length NS3 protease assay was prepared through a microwave-irradiated, palladium-catalyzed, amidocarbonylation protocol.
|
Inhibition of HCV NS3 serine protease
|
Hepatitis C virus
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Hepatitis C virus NS3-4A serine protease inhibitors: SAR of new P1 derivatives of SCH 503034.
Year : 2008
Volume : 18
Issue : 14
First Page : 4219
Last Page : 4223
Authors : Bogen S, Arasappan A, Pan W, Ruan S, Padilla A, Saksena AK, Girijavallabhan V, Njoroge FG.
Abstract : Substitutions on the P(1) cyclobutyl side chain of SCH 503034 were studied by introduction of hydroxyl and fluoro substituents. Additionally, effects of fluoro substitution on other P1 moieties were evaluated.
|
Inhibition of HCV NS3 protease in absence of human serum
|
Hepatitis C virus
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Second-generation highly potent and selective inhibitors of the hepatitis C virus NS3 serine protease.
Year : 2009
Volume : 52
Issue : 5
First Page : 1370
Last Page : 1379
Authors : Chen KX, Nair L, Vibulbhan B, Yang W, Arasappan A, Bogen SL, Venkatraman S, Bennett F, Pan W, Blackman ML, Padilla AI, Prongay A, Cheng KC, Tong X, Shih NY, Njoroge FG.
Abstract : The hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The moderate efficacy along with side effects of the current pegylated interferon and ribavirin combination therapy underscores the need for more effective and safer new treatment. In an effort to improve upon our current clinical candidate, Boceprevir (SCH 503034), extensive SAR studies were performed on the P3 capping moieties. This led to the discovery of tert-leucinol derived cyclic imides as a potent series of novel P3 capping groups. Thus, the introduction of these imide caps improved the cell-based replicon EC(90) by more than 10-fold. A number of imides with various substitutions, ring sizes, bicyclic systems, and heterocyclic rings were explored. The 4,4-dimethyl substituted glutarimide emerged as the best cap as exemplified in compound 21 (K(i)* = 4 nM, EC(90) = 40 nM). Systematic optimization of different positions (P', P3, and P1) of the inhibitor resulted in the identification of the lead compound 46, which had an excellent potency (K(i)* = 4 nM, EC(90) = 30 nM) and good pharmacokinetic profile (22% and 35% bioavailability in rats and dogs, respectively). X-ray structure of inhibitor 46 bound to the enzyme revealed that there was an additional hydrogen bonding interaction between one of the imide carbonyls and Cys159.
|
Binding affinity to HCV NS3 protease by spectrophotometry
|
Hepatitis C virus
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Toward second generation hepatitis C virus NS3 serine protease inhibitors: discovery of novel P4 modified analogues with improved potency and pharmacokinetic profile.
Year : 2009
Volume : 52
Issue : 9
First Page : 2806
Last Page : 2817
Authors : Arasappan A, Padilla AI, Jao E, Bennett F, Bogen SL, Chen KX, Pike RE, Sannigrahi M, Soares J, Venkatraman S, Vibulbhan B, Saksena AK, Girijavallabhan V, Tong X, Cheng KC, Njoroge FG.
Abstract : Hepatitis C virus (HCV) infection is a global health crisis leading to liver cirrhosis, hepatocellular carcinoma, and liver failure in humans. Recently, we disclosed the discovery of Boceprevir, SCH 503034 (1), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that is currently undergoing phase III clinical trials. Our efforts toward a second generation HCV NS3 serine protease inhibitor were directed at improving the overall profile of the inhibitor. This article will elaborate on our studies leading to the discovery of new P4 modified inhibitors with enhanced potency and improved oral bioavailability. Thus, introduction of ether and carbamate-derived P4 moieties resulted in improving the replicon potency significantly. Incorporation of the P' secondary amide residue afforded significant improvement in pharmacokinetic properties. Combining the preferred moieties, identified from comprehensive SAR studies, resulted in inhibitors that displayed superior potency and very good oral as well as target organ exposure in rats.
|
Binding affinity to HCV NS3 protease by spectrophotometry
|
Hepatitis C virus
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and evaluation of oxygen-containing macrocyclic peptidomimetics as inhibitors of HCV NS3 protease.
Year : 2009
Volume : 52
Issue : 3
First Page : 700
Last Page : 708
Authors : Velázquez F, Venkatraman S, Blackman M, Pinto P, Bogen S, Sannigrahi M, Chen K, Pichardo J, Hart A, Tong X, Girijavallabhan V, Njoroge FG.
Abstract : HCV infection is considered a silent epidemic because most people infected do not develop acute symptoms. Instead, the disease progresses to a chronic state leading to cirrhosis and hepatocarcinoma. Novel therapies are needed to combat this major health threat. The HCV NS3 serine protease has been the target of continuous investigation because of its pivotal role in viral replication. Herein, we present the P1-P3 macrocyclization approach followed for identification of HCV NS3 inhibitors as potential backup candidates to our first generation drug candidate, Sch 503034 (1). Different P1-P3 linkers were investigated to identify novel macrocyclic scaffolds. SAR exploration of P3-caps in the macrocyclic cores allowed the identification of l-serine derived macrocycle 32 (Ki* = 3 nM, EC90 = 30 nM) and allo-threonine derived macrocycle 36 (Ki* = 3 nM, EC90 = 30 nM) as potent HCV NS3 protease inhibitors.
|
Inhibition of HCV NS4A-tethered single chain NS3 serine protease by spectrophotometric assay
|
Hepatitis C virus
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Toward the back-up of boceprevir (SCH 503034): discovery of new extended P4-capped ketoamide inhibitors of hepatitis C virus NS3 serine protease with improved potency and pharmacokinetic profiles.
Year : 2009
Volume : 52
Issue : 12
First Page : 3679
Last Page : 3688
Authors : Bogen SL, Pan W, Ruan S, Nair LG, Arasappan A, Bennett F, Chen KX, Jao E, Venkatraman S, Vibulbhan B, Liu R, Cheng KC, Guo Z, Tong X, Saksena AK, Girijavallabhan V, Njoroge FG.
Abstract : Hepatitis C is the most prevalent liver disease. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically an estimated 300 million people worldwide. Results of Phase I clinical studies with our first generation HCV inhibitor Boceprevir, SCH 503034 (1), presented at the 56th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) were encouraging, and thus, additional human clinical studies are underway. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P(4) pocket and optimization of the P(1)' capping led to the discovery of new ketoamide inhibitors of the HCV NS3 serine protease with improved in vitro potency. In addition to being potent inhibitors of HCV subgenomic RNA replication, some of the new P(4)-capped inhibitors were also found to have improved PK profile.
|
Inhibition of HCV isolate BK NS4A-tethered single chain NS3 serine protease
|
Hepatitis C virus (isolate BK)
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel potent inhibitors of hepatitis C virus (HCV) NS3 protease with cyclic sulfonyl P3 cappings.
Year : 2009
Volume : 19
Issue : 4
First Page : 1105
Last Page : 1109
Authors : Chen KX, Vibulbhan B, Yang W, Nair LG, Tong X, Cheng KC, Njoroge FG.
Abstract : Extensive SAR studies of the P3 capping group led to the discovery of a series of potent inhibitors with sultam and cyclic sulfonyl urea moieties as the P3 capping. The bicyclic thiophene-sultam or phenyl-sultam cappings were selected for further SAR development. Modification at the P3 side chain determined that the tert-butyl group was the best choice at that position. Optimization of P1 residue significantly improved potency and selectivity. The combination of optimal moieties at all positions led to the discovery of compound 33. This compound had the best overall profile in potency and PK profile: excellent K(i)(*) of 5.3 nM and activity in replicon (EC(90)) of 80 nM, extremely high selectivity of 6100, and a good rat PO AUC of 1.43 microMh.
|
Inhibition of HCV NS3 protease assessed as hydrolysis of chromogenic 4-phenylazophenyl ester from peptide fragment Ac-DTEDVVP(Nva)-O-4-PAP by spectrophotometry
|
Hepatitis C virus
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Potent inhibitors of HCV-NS3 protease derived from boronic acids.
Year : 2009
Volume : 19
Issue : 1
First Page : 180
Last Page : 183
Authors : Venkatraman S, Wu W, Prongay A, Girijavallabhan V, George Njoroge F.
Abstract : Chronic hepatitis C infection is the leading causes for cirrhosis of the liver and hepatocellular carcinoma, leading to liver failure and liver transplantation. The etiological agent, HCV virus produces a single positive strand of RNA that is processed with the help of serine protease NS3 to produce mature virus. Inhibition of NS3 protease can be potentially used to develop effective drugs for HCV infections. Numerous efforts are now underway to develop potent inhibitors of HCV protease that contain ketoamides as serine traps. Herein we report the synthesis of a series of potent inhibitors that contain a boronic acid as a serine trap. The activity of these compounds were optimized to 200pM. X-ray structure of compound 17 bound to NS3 protease is also discussed.
|
Binding affinity to HCV NS3 protease
|
Hepatitis C virus
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and structure-activity relationship of P1-P3 ketoamide derived macrocyclic inhibitors of hepatitis C virus NS3 protease.
Year : 2009
Volume : 52
Issue : 2
First Page : 336
Last Page : 346
Authors : Venkatraman S, Velazquez F, Wu W, Blackman M, Chen KX, Bogen S, Nair L, Tong X, Chase R, Hart A, Agrawal S, Pichardo J, Prongay A, Cheng KC, Girijavallabhan V, Piwinski J, Shih NY, Njoroge FG.
Abstract : Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, and affects more than 200 million people worldwide. Although combination therapy of interferon-alpha and ribavirin is reasonably successful in treating majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of a series of ketoamide derived P(1)-P(3) macrocyclic inhibitors that are more potent than the first generation clinical candidate, boceprevir (1, Sch 503034), is discussed. The optimization of these macrocyclic inhibitors identified a P(3) imide capped analogue 52 that was 20 times more potent than 1 and demonstrated good oral pharmacokinetics in rats. X-ray structure of 52 bound to NS3 protease and biological data are also discussed.
|
Inhibition of full length HCV NS3/4A protease by TRF assay
|
Hepatitis C virus
|
35.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibitors of hepatitis C virus NS3/4A: alpha-ketoamide based macrocyclic inhibitors.
Year : 2009
Volume : 19
Issue : 8
First Page : 2295
Last Page : 2298
Authors : Avolio S, Robertson K, Hernando JI, DiMuzio J, Summa V.
Abstract : A novel series of hepatitis C virus (HCV) NS3/4A protease inhibitors bearing a P2-P4 macrocycle and a P1-P1' alpha-ketoamide serine trap is reported. The NS3 protease, which is essential for viral replication, is considered one of the most attractive targets for developing novel anti-HCV therapies. The optimization of both the macrocycle and the warhead portions led to the discovery of compounds 8b and 8 g with a good activity both in the enzyme as well as in the cell based (replicon) assays with favorable PK profile in a preclinical species.
|
Antiviral activity against HCV replication infected in human HuH7 cells after 72 hrs by replicon assay in presence of 5% FCS
|
Hepatitis C virus
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibitors of hepatitis C virus NS3/4A: alpha-ketoamide based macrocyclic inhibitors.
Year : 2009
Volume : 19
Issue : 8
First Page : 2295
Last Page : 2298
Authors : Avolio S, Robertson K, Hernando JI, DiMuzio J, Summa V.
Abstract : A novel series of hepatitis C virus (HCV) NS3/4A protease inhibitors bearing a P2-P4 macrocycle and a P1-P1' alpha-ketoamide serine trap is reported. The NS3 protease, which is essential for viral replication, is considered one of the most attractive targets for developing novel anti-HCV therapies. The optimization of both the macrocycle and the warhead portions led to the discovery of compounds 8b and 8 g with a good activity both in the enzyme as well as in the cell based (replicon) assays with favorable PK profile in a preclinical species.
|
Inhibition of HCV NS3 protease by continuous spectrophotometric assay
|
Hepatitis C virus
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Potent aza-peptide derived inhibitors of HCV NS3 protease.
Year : 2009
Volume : 19
Issue : 16
First Page : 4760
Last Page : 4763
Authors : Venkatraman S, Wu W, Shih NY, George Njoroge F.
Abstract : Chronic hepatitis C infection is the primary cause for cirrhosis of the liver and hepatocellular carcinoma leading to liver failure and transplantation. The etiological agent hepatitis C virus produces a single positive strand RNA that is processed further with the help of NS3 serine protease to produce mature virus. Inhibition of this protease can potentially be used to develop drugs for HCV infections. Boceprevir is a ketoamide derived novel inhibitor of HCV NS3 protease that has been progressed to clinical trials and proven to be efficacious in humans. Herein, we report our efforts in identifying an aza-peptide derivative as a potential second generation compound, that lacks electrophilic ketoamide group and are potent in enzyme and replicon assay.
|
Inhibition of HCV NS3 protease by continuous spectrophotometric assay
|
Hepatitis C virus
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of novel P3 sulfonamide-capped inhibitors of HCV NS3 protease. Inhibitors with improved cellular potencies.
Year : 2009
Volume : 17
Issue : 13
First Page : 4486
Last Page : 4495
Authors : Venkatraman S, Blackman M, Wu W, Nair L, Arasappan A, Padilla A, Bogen S, Bennett F, Chen K, Pichardo J, Tong X, Prongay A, Cheng KC, Girijavallabhan V, George Njoroge F.
Abstract : Hepatitis C Virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 200 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-alpha or PEG-interferon alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only approximately 50% of the patients showing sustained virological response. We recently disclosed the discovery of Boceprevir, SCH 503034 (1), which is a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been shown to be efficacious in humans and is currently undergoing clinical trials. As second generation compounds, we have further explored various novel structures with the aim of improving enzyme and cellular binding activities of 1. Herein, we disclose our efforts toward the identification of a novel P(3) sulfonamide-capped inhibitor that demonstrated improved binding and cellular activity compared to 1. X-ray structure of one of these inhibitors bound to the enzyme revealed a hydrogen bond of the P(3) sulfonamide group to Cys-159 which resulted in improved binding and cellular potency.
|
Inhibition of HCV NS4A-tethered single chain NS3 serine protease by spectrophotometric assay
|
Hepatitis C virus
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : P4 capped amides and lactams as HCV NS3 protease inhibitors with improved potency and DMPK profile.
Year : 2010
Volume : 20
Issue : 2
First Page : 567
Last Page : 570
Authors : Nair LG, Sannigrahi M, Bogen S, Pinto P, Chen KX, Prongay A, Tong X, Cheng KC, Girijavallabhan V, George Njoroge F.
Abstract : SAR studies on the extension of P3 unit of Boceprevir (1, SCH 503034) with amides and lactams and their synthesis is described. Extensive SAR studies resulted in the identification of 36 bearing 4, 4-dimethyl lactam as the new P4 cap unit with improved potency (K(i)( *)=15nM, EC 90=70nM) and pharmacokinetic properties (Rat AUC (PO)=3.52microMh) compared to 1.
|
Inhibition of HCV NS4A-tethered single chain NS3 serine protease assessed as Ac-DTEDVVP(Nva)- O-PAP substrate hydrolysis by spectrophotometric assay
|
Hepatitis C virus
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of potent sulfonamide P4-capped ketoamide second generation inhibitors of hepatitis C virus NS3 serine protease with favorable pharmacokinetic profiles in preclinical species.
Year : 2010
Volume : 18
Issue : 5
First Page : 1854
Last Page : 1865
Authors : Bogen SL, Arasappan A, Velazquez F, Blackman M, Huelgas R, Pan W, Siegel E, Nair LG, Venkatraman S, Guo Z, Doll R, Shih NY, Njoroge FG.
Abstract : Hepatitis is a disease characterized by inflammation of the liver, usually producing swelling and, in many cases, permanent damage to liver tissues. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically 3% of the world's population. Boceprevir, SCH 503034, (1) our first generation HCV inhibitor, has already established proof-of- concept and is currently in late stage (phase III) clinical trials. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P(4) pocket by introducing a new sulfonamide moiety and optimization of the P1/P(1)' capping led to the discovery of a novel series of inhibitors of the HCV NS3 serine protease. Optimization of the P(1) residue significantly improved potency and selectivity. The combination of optimal moieties led to the discovery of compound 47 which, in addition to being a potent inhibitor of HCV subgenomic RNA replication, was also found to have good PK profile in rat, dog and monkey.
|
Antiviral activity against Hepatitis C virus genotype 1 by replicon assay
|
Hepatitis C virus genotype 1
|
350.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of potent sulfonamide P4-capped ketoamide second generation inhibitors of hepatitis C virus NS3 serine protease with favorable pharmacokinetic profiles in preclinical species.
Year : 2010
Volume : 18
Issue : 5
First Page : 1854
Last Page : 1865
Authors : Bogen SL, Arasappan A, Velazquez F, Blackman M, Huelgas R, Pan W, Siegel E, Nair LG, Venkatraman S, Guo Z, Doll R, Shih NY, Njoroge FG.
Abstract : Hepatitis is a disease characterized by inflammation of the liver, usually producing swelling and, in many cases, permanent damage to liver tissues. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically 3% of the world's population. Boceprevir, SCH 503034, (1) our first generation HCV inhibitor, has already established proof-of- concept and is currently in late stage (phase III) clinical trials. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P(4) pocket by introducing a new sulfonamide moiety and optimization of the P1/P(1)' capping led to the discovery of a novel series of inhibitors of the HCV NS3 serine protease. Optimization of the P(1) residue significantly improved potency and selectivity. The combination of optimal moieties led to the discovery of compound 47 which, in addition to being a potent inhibitor of HCV subgenomic RNA replication, was also found to have good PK profile in rat, dog and monkey.
|
Inhibition of HCV NS3/4A serine protease by continuous spectrophotometric assay
|
Hepatitis C virus
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Towards the second generation of Boceprevir: Dithianes as an alternative P2 substituent for 2,2-dimethyl cycloproyl proline in HCV NS3 protease inhibitors.
Year : 2010
Volume : 20
Issue : 5
First Page : 1689
Last Page : 1692
Authors : Nair LG, Bogen S, Ruan S, Pan W, Pike R, Tong X, Cheng KC, Guo Z, Doll RJ, Njoroge FG.
Abstract : Hepatitis C (HCV) infection is a global health crisis leading to chronic liver disease. In our efforts towards a second generation HCV NS3 serine protease inhibitor with improved profile, we have undertaken SAR studies in various regions of Boceprevir including P2. Herein, we report the synthesis and structure-activity relationship studies of inhibitors with (S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid 2 as P2 substituent replacing the (1R,2S,5S)-6,6-dimethyl 3-azabicyclo[3.1.0]hexane-2-carboxylic acid. The systematic investigation led to the discovery of highly potent inhibitor 25 (K(i)( *)=7nM, EC(90)=30nM) with improved rat exposure of 2.56microM h.
|
Inhibition of Hepatitis C virus genotype 1 NS3 protease
|
Hepatitis C virus genotype 1
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Potent ketoamide inhibitors of HCV NS3 protease derived from quaternized P1 groups.
Year : 2010
Volume : 20
Issue : 7
First Page : 2151
Last Page : 2155
Authors : Venkatraman S, Velazquez F, Wu W, Blackman M, Madison V, Njoroge FG.
Abstract : Blood borne hepatitis C infections are the primary cause for liver cirrhosis and hepatocellular carcinoma. HCV NS3 protease, a pivotal enzyme in the replication cycle of HCV virus has been the primary target for development of new drug candidates. Boceprevir and telaprevir are two novel ketoamide derived inhibitors that are currently undergoing phase-III clinical trials. These inhibitors include ketoamide functionality as serine trap and have an acidic alpha-ketoamide center that undergoes epimerization under physiological conditions. Our initial attempts to arrest this epimerization by introducing quaternary amino acids at P(1) had resulted in significantly diminished activity. In this manuscript we describe alpha quaternized P(1) group that result in potent inhibitors in the enzyme assay and demonstrate cellular activity comparable to boceprevir.
|
Inhibition of HCV NS3/4A protease
|
Hepatitis C virus
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Cyclic sulfones as novel P3-caps for hepatitis C virus NS3/4A (HCV NS3/4A) protease inhibitors: synthesis and evaluation of inhibitors with improved potency and pharmacokinetic profiles.
Year : 2010
Volume : 53
Issue : 8
First Page : 3075
Last Page : 3085
Authors : Velázquez F, Sannigrahi M, Bennett F, Lovey RG, Arasappan A, Bogen S, Nair L, Venkatraman S, Blackman M, Hendrata S, Huang Y, Huelgas R, Pinto P, Cheng KC, Tong X, McPhail AT, Njoroge FG.
Abstract : HCV infection affects more than 170 million people worldwide and many of those patients will reach the end stage complications of the disease which include hepatocarcinoma and liver failure. The success rate for treatment of patients infected with genotype-1 is about 40%. Therefore, novel treatments are needed to combat the infection. The HCV NS3 protease inhibitor Boceprevir (1) was reported by our research group and efforts continue for the discovery of more potent compounds with improved pharmacokinetic profiles. A new series of HCV NS3 protease inhibitors having a cyclic sulfone P3-cap have been discovered. Compounds 43 and 44 showed K(i)* values in the single-digit nM range and their cellular potency was improved by 10-fold compared to 1. The pharmacokinetic profiles of 43 and 44 in rats and monkeys were also improved to achieve higher plasma levels after oral administration.
|
Inhibition of HCV NS4A tagged recombinant single chain NS3 protease after 15 mins
|
Hepatitis C virus
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The introduction of P4 substituted 1-methylcyclohexyl groups into Boceprevir: a change in direction in the search for a second generation HCV NS3 protease inhibitor.
Year : 2010
Volume : 20
Issue : 8
First Page : 2617
Last Page : 2621
Authors : Bennett F, Huang Y, Hendrata S, Lovey R, Bogen SL, Pan W, Guo Z, Prongay A, Chen KX, Arasappan A, Venkatraman S, Velazquez F, Nair L, Sannigrahi M, Tong X, Pichardo J, Cheng KC, Girijavallabhan VM, Saksena AK, Njoroge FG.
Abstract : In the search for a second generation HCV protease inhibitor, molecular modeling studies of the X-ray crystal structure of Boceprevir1 bound to the NS3 protein suggest that expansion into the S4 pocket could provide additional hydrophobic Van der Waals interactions. Effective replacement of the P4 tert-butyl with a cyclohexylmethyl ligand led to inhibitor 2 with improved enzyme and replicon activities. Subsequent modeling and SAR studies led to the pyridine 38 and sulfone analogues 52 and 53 with vastly improved PK parameters in monkeys, forming a new foundation for further exploration.
|
Inhibition of HCV NS3 protease by FRET assay
|
Hepatitis C virus
|
14.0
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 HCV 1B infected in human Huh7 cells by firefly luciferase reporter gene assay
|
Hepatitis C virus subtype 1b
|
200.0
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.
|
Inhibition of human Cathepsin S
|
Homo sapiens
|
120.0
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 human Cathepsin L
|
Homo sapiens
|
760.0
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 human Cathepsin V
|
Homo sapiens
|
75.0
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 human Chymase
|
Homo sapiens
|
32.0
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 human Cathepsin K
|
Homo sapiens
|
40.0
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 2a infected in mouse HB1 cell by cell-based HCV replicon assay in presence of 10% fetal bovine serum
|
Hepatitis C virus subtype 2a
|
170.0
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
|
480.0
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
|
21.0
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 2a NS3/4A protease activity
|
Hepatitis C virus subtype 2a
|
25.0
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
|
28.0
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 1a NS3/4A protease activity
|
Hepatitis C virus subtype 1a
|
21.0
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 human Huh-9-13 cells assessed as reduction in replicon RNA after 4days by RT-qPCR analysis
|
Hepatitis C virus subtype 1b
|
130.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Comparative in vitro anti-hepatitis C virus activities of a selected series of polymerase, protease, and helicase inhibitors.
Year : 2008
Volume : 52
Issue : 9
First Page : 3433
Last Page : 3437
Authors : Paeshuyse J, Vliegen I, Coelmont L, Leyssen P, Tabarrini O, Herdewijn P, Mittendorfer H, Easmon J, Cecchetti V, Bartenschlager R, Puerstinger G, Neyts J.
Abstract : We report here a comparative study of the anti-hepatitis C virus (HCV) activities of selected (i) nucleoside polymerase, (ii) nonnucleoside polymerase, (iii) alpha,gamma-diketo acid polymerase, (iv) NS3 protease, and (v) helicase inhibitors, as well as (vi) cyclophilin binding molecules and (vii) alpha 2b interferon in four different HCV genotype 1b replicon systems.
|
Antiviral activity against Hepatitis C virus genotype 1b infected in human HuH6 cells assessed as reduction in replicon RNA after 4days by RT-qPCR analysis
|
Hepatitis C virus subtype 1b
|
350.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Comparative in vitro anti-hepatitis C virus activities of a selected series of polymerase, protease, and helicase inhibitors.
Year : 2008
Volume : 52
Issue : 9
First Page : 3433
Last Page : 3437
Authors : Paeshuyse J, Vliegen I, Coelmont L, Leyssen P, Tabarrini O, Herdewijn P, Mittendorfer H, Easmon J, Cecchetti V, Bartenschlager R, Puerstinger G, Neyts J.
Abstract : We report here a comparative study of the anti-hepatitis C virus (HCV) activities of selected (i) nucleoside polymerase, (ii) nonnucleoside polymerase, (iii) alpha,gamma-diketo acid polymerase, (iv) NS3 protease, and (v) helicase inhibitors, as well as (vi) cyclophilin binding molecules and (vii) alpha 2b interferon in four different HCV genotype 1b replicon systems.
|
Inhibition of HCV 1a NS3/4A protease
|
Hepatitis C virus subtype 1a
|
1.1
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Preclinical characterization of BI 201335, a C-terminal carboxylic acid inhibitor of the hepatitis C virus NS3-NS4A protease.
Year : 2010
Volume : 54
Issue : 11
First Page : 4611
Last Page : 4618
Authors : White PW, Llinàs-Brunet M, Amad M, Bethell RC, Bolger G, Cordingley MG, Duan J, Garneau M, Lagacé L, Thibeault D, Kukolj G.
Abstract : BI 201335 is a hepatitis C virus (HCV) NS3-NS4A (NS3 coexpressed with NS4A) protease inhibitor that has been shown to have potent clinical antiviral activity. It is a highly optimized noncovalent competitive inhibitor of full-length NS3-NS4A proteases of HCV genotypes 1a and 1b with K(i) values of 2.6 and 2.0 nM, respectively. K(i) values of 2 to 230 nM were measured against the NS3-NS4A proteases of HCV genotypes 2 to 6, whereas it was a very weak inhibitor of cathepsin B and showed no measurable inhibition of human leukocyte elastase. BI 201335 was also shown to be a potent inhibitor of HCV RNA replication in vitro with 50% effective concentrations (EC(50)s) of 6.5 and 3.1 nM obtained in genotype 1a and 1b replicon assays. Combinations of BI 201335 with either interferon or ribavirin had additive effects in replicon assays. BI 201335 had good permeability in Caco-2 cell assays and high metabolic stability after incubation with human, rat, monkey, and dog liver microsomes. Its good absorption, distribution, metabolism, and excretion (ADME) profile in vitro, as well as in rat, monkey, and dog, predicted good pharmacokinetics (PK) in humans. Furthermore, drug levels were significantly higher in rat liver than in plasma, suggesting that distribution to the target organ may be especially favorable. BI 201335 is a highly potent and selective NS3-NS4A protease inhibitor with good in vitro and animal ADME properties, consistent with its good human PK profile, and shows great promise as a treatment for HCV infection.
|
Inhibition of HCV 1b NS3/4A protease
|
Hepatitis C virus subtype 1b
|
2.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Preclinical characterization of BI 201335, a C-terminal carboxylic acid inhibitor of the hepatitis C virus NS3-NS4A protease.
Year : 2010
Volume : 54
Issue : 11
First Page : 4611
Last Page : 4618
Authors : White PW, Llinàs-Brunet M, Amad M, Bethell RC, Bolger G, Cordingley MG, Duan J, Garneau M, Lagacé L, Thibeault D, Kukolj G.
Abstract : BI 201335 is a hepatitis C virus (HCV) NS3-NS4A (NS3 coexpressed with NS4A) protease inhibitor that has been shown to have potent clinical antiviral activity. It is a highly optimized noncovalent competitive inhibitor of full-length NS3-NS4A proteases of HCV genotypes 1a and 1b with K(i) values of 2.6 and 2.0 nM, respectively. K(i) values of 2 to 230 nM were measured against the NS3-NS4A proteases of HCV genotypes 2 to 6, whereas it was a very weak inhibitor of cathepsin B and showed no measurable inhibition of human leukocyte elastase. BI 201335 was also shown to be a potent inhibitor of HCV RNA replication in vitro with 50% effective concentrations (EC(50)s) of 6.5 and 3.1 nM obtained in genotype 1a and 1b replicon assays. Combinations of BI 201335 with either interferon or ribavirin had additive effects in replicon assays. BI 201335 had good permeability in Caco-2 cell assays and high metabolic stability after incubation with human, rat, monkey, and dog liver microsomes. Its good absorption, distribution, metabolism, and excretion (ADME) profile in vitro, as well as in rat, monkey, and dog, predicted good pharmacokinetics (PK) in humans. Furthermore, drug levels were significantly higher in rat liver than in plasma, suggesting that distribution to the target organ may be especially favorable. BI 201335 is a highly potent and selective NS3-NS4A protease inhibitor with good in vitro and animal ADME properties, consistent with its good human PK profile, and shows great promise as a treatment for HCV infection.
|
Inhibition of HCV 2a NS3/4A protease
|
Hepatitis C virus subtype 2a
|
7.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Preclinical characterization of BI 201335, a C-terminal carboxylic acid inhibitor of the hepatitis C virus NS3-NS4A protease.
Year : 2010
Volume : 54
Issue : 11
First Page : 4611
Last Page : 4618
Authors : White PW, Llinàs-Brunet M, Amad M, Bethell RC, Bolger G, Cordingley MG, Duan J, Garneau M, Lagacé L, Thibeault D, Kukolj G.
Abstract : BI 201335 is a hepatitis C virus (HCV) NS3-NS4A (NS3 coexpressed with NS4A) protease inhibitor that has been shown to have potent clinical antiviral activity. It is a highly optimized noncovalent competitive inhibitor of full-length NS3-NS4A proteases of HCV genotypes 1a and 1b with K(i) values of 2.6 and 2.0 nM, respectively. K(i) values of 2 to 230 nM were measured against the NS3-NS4A proteases of HCV genotypes 2 to 6, whereas it was a very weak inhibitor of cathepsin B and showed no measurable inhibition of human leukocyte elastase. BI 201335 was also shown to be a potent inhibitor of HCV RNA replication in vitro with 50% effective concentrations (EC(50)s) of 6.5 and 3.1 nM obtained in genotype 1a and 1b replicon assays. Combinations of BI 201335 with either interferon or ribavirin had additive effects in replicon assays. BI 201335 had good permeability in Caco-2 cell assays and high metabolic stability after incubation with human, rat, monkey, and dog liver microsomes. Its good absorption, distribution, metabolism, and excretion (ADME) profile in vitro, as well as in rat, monkey, and dog, predicted good pharmacokinetics (PK) in humans. Furthermore, drug levels were significantly higher in rat liver than in plasma, suggesting that distribution to the target organ may be especially favorable. BI 201335 is a highly potent and selective NS3-NS4A protease inhibitor with good in vitro and animal ADME properties, consistent with its good human PK profile, and shows great promise as a treatment for HCV infection.
|
Inhibition of HCV 2b NS3/4A protease
|
Hepatitis C virus subtype 2b
|
28.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Preclinical characterization of BI 201335, a C-terminal carboxylic acid inhibitor of the hepatitis C virus NS3-NS4A protease.
Year : 2010
Volume : 54
Issue : 11
First Page : 4611
Last Page : 4618
Authors : White PW, Llinàs-Brunet M, Amad M, Bethell RC, Bolger G, Cordingley MG, Duan J, Garneau M, Lagacé L, Thibeault D, Kukolj G.
Abstract : BI 201335 is a hepatitis C virus (HCV) NS3-NS4A (NS3 coexpressed with NS4A) protease inhibitor that has been shown to have potent clinical antiviral activity. It is a highly optimized noncovalent competitive inhibitor of full-length NS3-NS4A proteases of HCV genotypes 1a and 1b with K(i) values of 2.6 and 2.0 nM, respectively. K(i) values of 2 to 230 nM were measured against the NS3-NS4A proteases of HCV genotypes 2 to 6, whereas it was a very weak inhibitor of cathepsin B and showed no measurable inhibition of human leukocyte elastase. BI 201335 was also shown to be a potent inhibitor of HCV RNA replication in vitro with 50% effective concentrations (EC(50)s) of 6.5 and 3.1 nM obtained in genotype 1a and 1b replicon assays. Combinations of BI 201335 with either interferon or ribavirin had additive effects in replicon assays. BI 201335 had good permeability in Caco-2 cell assays and high metabolic stability after incubation with human, rat, monkey, and dog liver microsomes. Its good absorption, distribution, metabolism, and excretion (ADME) profile in vitro, as well as in rat, monkey, and dog, predicted good pharmacokinetics (PK) in humans. Furthermore, drug levels were significantly higher in rat liver than in plasma, suggesting that distribution to the target organ may be especially favorable. BI 201335 is a highly potent and selective NS3-NS4A protease inhibitor with good in vitro and animal ADME properties, consistent with its good human PK profile, and shows great promise as a treatment for HCV infection.
|
Inhibition of HCV 3a NS3/4A protease
|
Hepatitis C virus subtype 3a
|
23.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Preclinical characterization of BI 201335, a C-terminal carboxylic acid inhibitor of the hepatitis C virus NS3-NS4A protease.
Year : 2010
Volume : 54
Issue : 11
First Page : 4611
Last Page : 4618
Authors : White PW, Llinàs-Brunet M, Amad M, Bethell RC, Bolger G, Cordingley MG, Duan J, Garneau M, Lagacé L, Thibeault D, Kukolj G.
Abstract : BI 201335 is a hepatitis C virus (HCV) NS3-NS4A (NS3 coexpressed with NS4A) protease inhibitor that has been shown to have potent clinical antiviral activity. It is a highly optimized noncovalent competitive inhibitor of full-length NS3-NS4A proteases of HCV genotypes 1a and 1b with K(i) values of 2.6 and 2.0 nM, respectively. K(i) values of 2 to 230 nM were measured against the NS3-NS4A proteases of HCV genotypes 2 to 6, whereas it was a very weak inhibitor of cathepsin B and showed no measurable inhibition of human leukocyte elastase. BI 201335 was also shown to be a potent inhibitor of HCV RNA replication in vitro with 50% effective concentrations (EC(50)s) of 6.5 and 3.1 nM obtained in genotype 1a and 1b replicon assays. Combinations of BI 201335 with either interferon or ribavirin had additive effects in replicon assays. BI 201335 had good permeability in Caco-2 cell assays and high metabolic stability after incubation with human, rat, monkey, and dog liver microsomes. Its good absorption, distribution, metabolism, and excretion (ADME) profile in vitro, as well as in rat, monkey, and dog, predicted good pharmacokinetics (PK) in humans. Furthermore, drug levels were significantly higher in rat liver than in plasma, suggesting that distribution to the target organ may be especially favorable. BI 201335 is a highly potent and selective NS3-NS4A protease inhibitor with good in vitro and animal ADME properties, consistent with its good human PK profile, and shows great promise as a treatment for HCV infection.
|
Inhibition of HCV 4a NS3/4A protease
|
Hepatitis C virus subtype 4a
|
8.6
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Preclinical characterization of BI 201335, a C-terminal carboxylic acid inhibitor of the hepatitis C virus NS3-NS4A protease.
Year : 2010
Volume : 54
Issue : 11
First Page : 4611
Last Page : 4618
Authors : White PW, Llinàs-Brunet M, Amad M, Bethell RC, Bolger G, Cordingley MG, Duan J, Garneau M, Lagacé L, Thibeault D, Kukolj G.
Abstract : BI 201335 is a hepatitis C virus (HCV) NS3-NS4A (NS3 coexpressed with NS4A) protease inhibitor that has been shown to have potent clinical antiviral activity. It is a highly optimized noncovalent competitive inhibitor of full-length NS3-NS4A proteases of HCV genotypes 1a and 1b with K(i) values of 2.6 and 2.0 nM, respectively. K(i) values of 2 to 230 nM were measured against the NS3-NS4A proteases of HCV genotypes 2 to 6, whereas it was a very weak inhibitor of cathepsin B and showed no measurable inhibition of human leukocyte elastase. BI 201335 was also shown to be a potent inhibitor of HCV RNA replication in vitro with 50% effective concentrations (EC(50)s) of 6.5 and 3.1 nM obtained in genotype 1a and 1b replicon assays. Combinations of BI 201335 with either interferon or ribavirin had additive effects in replicon assays. BI 201335 had good permeability in Caco-2 cell assays and high metabolic stability after incubation with human, rat, monkey, and dog liver microsomes. Its good absorption, distribution, metabolism, and excretion (ADME) profile in vitro, as well as in rat, monkey, and dog, predicted good pharmacokinetics (PK) in humans. Furthermore, drug levels were significantly higher in rat liver than in plasma, suggesting that distribution to the target organ may be especially favorable. BI 201335 is a highly potent and selective NS3-NS4A protease inhibitor with good in vitro and animal ADME properties, consistent with its good human PK profile, and shows great promise as a treatment for HCV infection.
|
Inhibition of HCV 6a NS3/4A protease
|
Hepatitis C virus subtype 6a
|
2.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Preclinical characterization of BI 201335, a C-terminal carboxylic acid inhibitor of the hepatitis C virus NS3-NS4A protease.
Year : 2010
Volume : 54
Issue : 11
First Page : 4611
Last Page : 4618
Authors : White PW, Llinàs-Brunet M, Amad M, Bethell RC, Bolger G, Cordingley MG, Duan J, Garneau M, Lagacé L, Thibeault D, Kukolj G.
Abstract : BI 201335 is a hepatitis C virus (HCV) NS3-NS4A (NS3 coexpressed with NS4A) protease inhibitor that has been shown to have potent clinical antiviral activity. It is a highly optimized noncovalent competitive inhibitor of full-length NS3-NS4A proteases of HCV genotypes 1a and 1b with K(i) values of 2.6 and 2.0 nM, respectively. K(i) values of 2 to 230 nM were measured against the NS3-NS4A proteases of HCV genotypes 2 to 6, whereas it was a very weak inhibitor of cathepsin B and showed no measurable inhibition of human leukocyte elastase. BI 201335 was also shown to be a potent inhibitor of HCV RNA replication in vitro with 50% effective concentrations (EC(50)s) of 6.5 and 3.1 nM obtained in genotype 1a and 1b replicon assays. Combinations of BI 201335 with either interferon or ribavirin had additive effects in replicon assays. BI 201335 had good permeability in Caco-2 cell assays and high metabolic stability after incubation with human, rat, monkey, and dog liver microsomes. Its good absorption, distribution, metabolism, and excretion (ADME) profile in vitro, as well as in rat, monkey, and dog, predicted good pharmacokinetics (PK) in humans. Furthermore, drug levels were significantly higher in rat liver than in plasma, suggesting that distribution to the target organ may be especially favorable. BI 201335 is a highly potent and selective NS3-NS4A protease inhibitor with good in vitro and animal ADME properties, consistent with its good human PK profile, and shows great promise as a treatment for HCV infection.
|
Binding affinity to HCV 5a NS3/4A protease
|
Hepatitis C virus subtype 5a
|
18.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Preclinical characterization of BI 201335, a C-terminal carboxylic acid inhibitor of the hepatitis C virus NS3-NS4A protease.
Year : 2010
Volume : 54
Issue : 11
First Page : 4611
Last Page : 4618
Authors : White PW, Llinàs-Brunet M, Amad M, Bethell RC, Bolger G, Cordingley MG, Duan J, Garneau M, Lagacé L, Thibeault D, Kukolj G.
Abstract : BI 201335 is a hepatitis C virus (HCV) NS3-NS4A (NS3 coexpressed with NS4A) protease inhibitor that has been shown to have potent clinical antiviral activity. It is a highly optimized noncovalent competitive inhibitor of full-length NS3-NS4A proteases of HCV genotypes 1a and 1b with K(i) values of 2.6 and 2.0 nM, respectively. K(i) values of 2 to 230 nM were measured against the NS3-NS4A proteases of HCV genotypes 2 to 6, whereas it was a very weak inhibitor of cathepsin B and showed no measurable inhibition of human leukocyte elastase. BI 201335 was also shown to be a potent inhibitor of HCV RNA replication in vitro with 50% effective concentrations (EC(50)s) of 6.5 and 3.1 nM obtained in genotype 1a and 1b replicon assays. Combinations of BI 201335 with either interferon or ribavirin had additive effects in replicon assays. BI 201335 had good permeability in Caco-2 cell assays and high metabolic stability after incubation with human, rat, monkey, and dog liver microsomes. Its good absorption, distribution, metabolism, and excretion (ADME) profile in vitro, as well as in rat, monkey, and dog, predicted good pharmacokinetics (PK) in humans. Furthermore, drug levels were significantly higher in rat liver than in plasma, suggesting that distribution to the target organ may be especially favorable. BI 201335 is a highly potent and selective NS3-NS4A protease inhibitor with good in vitro and animal ADME properties, consistent with its good human PK profile, and shows great promise as a treatment for HCV infection.
|
Antiviral activity against HCV 1a infected in Huh7 cells assessed as inhibition of viral replication after 72 hrs by RT-PCR
|
Hepatitis C virus subtype 1a
|
550.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Preclinical characterization of BI 201335, a C-terminal carboxylic acid inhibitor of the hepatitis C virus NS3-NS4A protease.
Year : 2010
Volume : 54
Issue : 11
First Page : 4611
Last Page : 4618
Authors : White PW, Llinàs-Brunet M, Amad M, Bethell RC, Bolger G, Cordingley MG, Duan J, Garneau M, Lagacé L, Thibeault D, Kukolj G.
Abstract : BI 201335 is a hepatitis C virus (HCV) NS3-NS4A (NS3 coexpressed with NS4A) protease inhibitor that has been shown to have potent clinical antiviral activity. It is a highly optimized noncovalent competitive inhibitor of full-length NS3-NS4A proteases of HCV genotypes 1a and 1b with K(i) values of 2.6 and 2.0 nM, respectively. K(i) values of 2 to 230 nM were measured against the NS3-NS4A proteases of HCV genotypes 2 to 6, whereas it was a very weak inhibitor of cathepsin B and showed no measurable inhibition of human leukocyte elastase. BI 201335 was also shown to be a potent inhibitor of HCV RNA replication in vitro with 50% effective concentrations (EC(50)s) of 6.5 and 3.1 nM obtained in genotype 1a and 1b replicon assays. Combinations of BI 201335 with either interferon or ribavirin had additive effects in replicon assays. BI 201335 had good permeability in Caco-2 cell assays and high metabolic stability after incubation with human, rat, monkey, and dog liver microsomes. Its good absorption, distribution, metabolism, and excretion (ADME) profile in vitro, as well as in rat, monkey, and dog, predicted good pharmacokinetics (PK) in humans. Furthermore, drug levels were significantly higher in rat liver than in plasma, suggesting that distribution to the target organ may be especially favorable. BI 201335 is a highly potent and selective NS3-NS4A protease inhibitor with good in vitro and animal ADME properties, consistent with its good human PK profile, and shows great promise as a treatment for HCV infection.
|
Antiviral activity against HCV 1b infected in Huh7 cells assessed as inhibition of viral replication after 72 hrs by RT-PCR
|
Hepatitis C virus subtype 1b
|
520.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Preclinical characterization of BI 201335, a C-terminal carboxylic acid inhibitor of the hepatitis C virus NS3-NS4A protease.
Year : 2010
Volume : 54
Issue : 11
First Page : 4611
Last Page : 4618
Authors : White PW, Llinàs-Brunet M, Amad M, Bethell RC, Bolger G, Cordingley MG, Duan J, Garneau M, Lagacé L, Thibeault D, Kukolj G.
Abstract : BI 201335 is a hepatitis C virus (HCV) NS3-NS4A (NS3 coexpressed with NS4A) protease inhibitor that has been shown to have potent clinical antiviral activity. It is a highly optimized noncovalent competitive inhibitor of full-length NS3-NS4A proteases of HCV genotypes 1a and 1b with K(i) values of 2.6 and 2.0 nM, respectively. K(i) values of 2 to 230 nM were measured against the NS3-NS4A proteases of HCV genotypes 2 to 6, whereas it was a very weak inhibitor of cathepsin B and showed no measurable inhibition of human leukocyte elastase. BI 201335 was also shown to be a potent inhibitor of HCV RNA replication in vitro with 50% effective concentrations (EC(50)s) of 6.5 and 3.1 nM obtained in genotype 1a and 1b replicon assays. Combinations of BI 201335 with either interferon or ribavirin had additive effects in replicon assays. BI 201335 had good permeability in Caco-2 cell assays and high metabolic stability after incubation with human, rat, monkey, and dog liver microsomes. Its good absorption, distribution, metabolism, and excretion (ADME) profile in vitro, as well as in rat, monkey, and dog, predicted good pharmacokinetics (PK) in humans. Furthermore, drug levels were significantly higher in rat liver than in plasma, suggesting that distribution to the target organ may be especially favorable. BI 201335 is a highly potent and selective NS3-NS4A protease inhibitor with good in vitro and animal ADME properties, consistent with its good human PK profile, and shows great promise as a treatment for HCV infection.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing WT NS3 infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
148.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 V36L mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
110.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 V36M mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
217.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 F43S mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
333.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 F43I mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
242.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 F43V mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
527.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 T54A mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
268.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q80R mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
85.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q80H mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
78.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q80K mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
94.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q80G mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
127.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q80L mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
133.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 R109K mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
33.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 S138T mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
16.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 R155M mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
792.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 R155Q mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
174.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 R155K mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
743.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 A156S mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
525.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 A156G mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
65.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 D168G mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
63.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 D168N mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
101.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 D168E mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
69.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 D168T mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
299.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 D168Y mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
193.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 D168H mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
73.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 D168A mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
100.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 D168V mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
83.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 D168I mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
279.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 V170T mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
210.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 F43S and D168E mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
417.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q80R and R155K mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
680.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q80R and D168E mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
62.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q80H and D168E mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
20.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q80R and D168A mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
113.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus genotype 1b Con1 infected in human HuH7.5 cells after 72 hrs by gaussia luciferase reporter assay
|
Hepatitis C virus
|
608.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Selection and characterization of hepatitis C virus replicons dually resistant to the polymerase and protease inhibitors HCV-796 and boceprevir (SCH 503034).
Year : 2009
Volume : 53
Issue : 2
First Page : 401
Last Page : 411
Authors : Flint M, Mullen S, Deatly AM, Chen W, Miller LZ, Ralston R, Broom C, Emini EA, Howe AY.
Abstract : HCV-796 is a nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) polymerase, and boceprevir is an inhibitor of the NS3 serine protease. The emergence of replicon variants resistant to the combination of HCV-796 and boceprevir was evaluated. Combining the inhibitors greatly reduced the frequency with which resistant colonies arose; however, some resistant replicon cells could be isolated by the use of low inhibitor concentrations. These replicons were approximately 1,000-fold less susceptible to HCV-796 and 9-fold less susceptible to boceprevir. They also exhibited resistance to anthranilate nonnucleoside inhibitors of NS5B but were fully sensitive to inhibitors of different mechanisms: a pyranoindole, Hsp90 inhibitors, an NS5B nucleoside inhibitor, and pegylated interferon (Peg-IFN). The replicon was cleared from the combination-resistant cells by extended treatment with Peg-IFN. Mutations known to confer resistance to HCV-796 (NS5B C316Y) and boceprevir (NS3 V170A) were present in the combination-resistant replicons. These changes could be selected together and coexist in the same genome. The replicon bearing both changes exhibited reduced sensitivity to inhibition by HCV-796 and boceprevir but had a reduced replicative capacity.
|
Antiviral activity against Hepatitis C virus genotype 1b Con1 infected in human HuH7 cells assessed as GAPDH RNA or 18S rRNA level after 3 days by qRT-PCR analysis
|
Hepatitis C virus
|
165.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Selection and characterization of hepatitis C virus replicons dually resistant to the polymerase and protease inhibitors HCV-796 and boceprevir (SCH 503034).
Year : 2009
Volume : 53
Issue : 2
First Page : 401
Last Page : 411
Authors : Flint M, Mullen S, Deatly AM, Chen W, Miller LZ, Ralston R, Broom C, Emini EA, Howe AY.
Abstract : HCV-796 is a nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) polymerase, and boceprevir is an inhibitor of the NS3 serine protease. The emergence of replicon variants resistant to the combination of HCV-796 and boceprevir was evaluated. Combining the inhibitors greatly reduced the frequency with which resistant colonies arose; however, some resistant replicon cells could be isolated by the use of low inhibitor concentrations. These replicons were approximately 1,000-fold less susceptible to HCV-796 and 9-fold less susceptible to boceprevir. They also exhibited resistance to anthranilate nonnucleoside inhibitors of NS5B but were fully sensitive to inhibitors of different mechanisms: a pyranoindole, Hsp90 inhibitors, an NS5B nucleoside inhibitor, and pegylated interferon (Peg-IFN). The replicon was cleared from the combination-resistant cells by extended treatment with Peg-IFN. Mutations known to confer resistance to HCV-796 (NS5B C316Y) and boceprevir (NS3 V170A) were present in the combination-resistant replicons. These changes could be selected together and coexist in the same genome. The replicon bearing both changes exhibited reduced sensitivity to inhibition by HCV-796 and boceprevir but had a reduced replicative capacity.
|
Antiviral activity against Hepatitis C virus genotype 1b Con1 harboring NS3 V158M mutant infected in human HuH7.5 cells after 72 hrs by gaussia luciferase reporter assay
|
Hepatitis C virus
|
377.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Selection and characterization of hepatitis C virus replicons dually resistant to the polymerase and protease inhibitors HCV-796 and boceprevir (SCH 503034).
Year : 2009
Volume : 53
Issue : 2
First Page : 401
Last Page : 411
Authors : Flint M, Mullen S, Deatly AM, Chen W, Miller LZ, Ralston R, Broom C, Emini EA, Howe AY.
Abstract : HCV-796 is a nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) polymerase, and boceprevir is an inhibitor of the NS3 serine protease. The emergence of replicon variants resistant to the combination of HCV-796 and boceprevir was evaluated. Combining the inhibitors greatly reduced the frequency with which resistant colonies arose; however, some resistant replicon cells could be isolated by the use of low inhibitor concentrations. These replicons were approximately 1,000-fold less susceptible to HCV-796 and 9-fold less susceptible to boceprevir. They also exhibited resistance to anthranilate nonnucleoside inhibitors of NS5B but were fully sensitive to inhibitors of different mechanisms: a pyranoindole, Hsp90 inhibitors, an NS5B nucleoside inhibitor, and pegylated interferon (Peg-IFN). The replicon was cleared from the combination-resistant cells by extended treatment with Peg-IFN. Mutations known to confer resistance to HCV-796 (NS5B C316Y) and boceprevir (NS3 V170A) were present in the combination-resistant replicons. These changes could be selected together and coexist in the same genome. The replicon bearing both changes exhibited reduced sensitivity to inhibition by HCV-796 and boceprevir but had a reduced replicative capacity.
|
Antiviral activity against Hepatitis C virus genotype 1b Con1 harboring NS3 K583T mutant infected in human HuH7.5 cells after 72 hrs by gaussia luciferase reporter assay
|
Hepatitis C virus
|
738.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Selection and characterization of hepatitis C virus replicons dually resistant to the polymerase and protease inhibitors HCV-796 and boceprevir (SCH 503034).
Year : 2009
Volume : 53
Issue : 2
First Page : 401
Last Page : 411
Authors : Flint M, Mullen S, Deatly AM, Chen W, Miller LZ, Ralston R, Broom C, Emini EA, Howe AY.
Abstract : HCV-796 is a nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) polymerase, and boceprevir is an inhibitor of the NS3 serine protease. The emergence of replicon variants resistant to the combination of HCV-796 and boceprevir was evaluated. Combining the inhibitors greatly reduced the frequency with which resistant colonies arose; however, some resistant replicon cells could be isolated by the use of low inhibitor concentrations. These replicons were approximately 1,000-fold less susceptible to HCV-796 and 9-fold less susceptible to boceprevir. They also exhibited resistance to anthranilate nonnucleoside inhibitors of NS5B but were fully sensitive to inhibitors of different mechanisms: a pyranoindole, Hsp90 inhibitors, an NS5B nucleoside inhibitor, and pegylated interferon (Peg-IFN). The replicon was cleared from the combination-resistant cells by extended treatment with Peg-IFN. Mutations known to confer resistance to HCV-796 (NS5B C316Y) and boceprevir (NS3 V170A) were present in the combination-resistant replicons. These changes could be selected together and coexist in the same genome. The replicon bearing both changes exhibited reduced sensitivity to inhibition by HCV-796 and boceprevir but had a reduced replicative capacity.
|
Antiviral activity against Hepatitis C virus genotype 1b Con1 harboring NS5B C316Y mutant infected in human HuH7.5 cells after 72 hrs by gaussia luciferase reporter assay
|
Hepatitis C virus
|
781.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Selection and characterization of hepatitis C virus replicons dually resistant to the polymerase and protease inhibitors HCV-796 and boceprevir (SCH 503034).
Year : 2009
Volume : 53
Issue : 2
First Page : 401
Last Page : 411
Authors : Flint M, Mullen S, Deatly AM, Chen W, Miller LZ, Ralston R, Broom C, Emini EA, Howe AY.
Abstract : HCV-796 is a nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) polymerase, and boceprevir is an inhibitor of the NS3 serine protease. The emergence of replicon variants resistant to the combination of HCV-796 and boceprevir was evaluated. Combining the inhibitors greatly reduced the frequency with which resistant colonies arose; however, some resistant replicon cells could be isolated by the use of low inhibitor concentrations. These replicons were approximately 1,000-fold less susceptible to HCV-796 and 9-fold less susceptible to boceprevir. They also exhibited resistance to anthranilate nonnucleoside inhibitors of NS5B but were fully sensitive to inhibitors of different mechanisms: a pyranoindole, Hsp90 inhibitors, an NS5B nucleoside inhibitor, and pegylated interferon (Peg-IFN). The replicon was cleared from the combination-resistant cells by extended treatment with Peg-IFN. Mutations known to confer resistance to HCV-796 (NS5B C316Y) and boceprevir (NS3 V170A) were present in the combination-resistant replicons. These changes could be selected together and coexist in the same genome. The replicon bearing both changes exhibited reduced sensitivity to inhibition by HCV-796 and boceprevir but had a reduced replicative capacity.
|
Antiviral activity against Hepatitis C virus genotype 1b Con1 harboring NS5B I424V mutant infected in human HuH7.5 cells after 72 hrs by gaussia luciferase reporter assay
|
Hepatitis C virus
|
647.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Selection and characterization of hepatitis C virus replicons dually resistant to the polymerase and protease inhibitors HCV-796 and boceprevir (SCH 503034).
Year : 2009
Volume : 53
Issue : 2
First Page : 401
Last Page : 411
Authors : Flint M, Mullen S, Deatly AM, Chen W, Miller LZ, Ralston R, Broom C, Emini EA, Howe AY.
Abstract : HCV-796 is a nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) polymerase, and boceprevir is an inhibitor of the NS3 serine protease. The emergence of replicon variants resistant to the combination of HCV-796 and boceprevir was evaluated. Combining the inhibitors greatly reduced the frequency with which resistant colonies arose; however, some resistant replicon cells could be isolated by the use of low inhibitor concentrations. These replicons were approximately 1,000-fold less susceptible to HCV-796 and 9-fold less susceptible to boceprevir. They also exhibited resistance to anthranilate nonnucleoside inhibitors of NS5B but were fully sensitive to inhibitors of different mechanisms: a pyranoindole, Hsp90 inhibitors, an NS5B nucleoside inhibitor, and pegylated interferon (Peg-IFN). The replicon was cleared from the combination-resistant cells by extended treatment with Peg-IFN. Mutations known to confer resistance to HCV-796 (NS5B C316Y) and boceprevir (NS3 V170A) were present in the combination-resistant replicons. These changes could be selected together and coexist in the same genome. The replicon bearing both changes exhibited reduced sensitivity to inhibition by HCV-796 and boceprevir but had a reduced replicative capacity.
|
Antiviral activity against Hepatitis C virus genotype 1b Con1 harboring NS5B C445F mutant infected in human HuH7.5 cells after 72 hrs by gaussia luciferase reporter assay
|
Hepatitis C virus
|
795.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Selection and characterization of hepatitis C virus replicons dually resistant to the polymerase and protease inhibitors HCV-796 and boceprevir (SCH 503034).
Year : 2009
Volume : 53
Issue : 2
First Page : 401
Last Page : 411
Authors : Flint M, Mullen S, Deatly AM, Chen W, Miller LZ, Ralston R, Broom C, Emini EA, Howe AY.
Abstract : HCV-796 is a nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) polymerase, and boceprevir is an inhibitor of the NS3 serine protease. The emergence of replicon variants resistant to the combination of HCV-796 and boceprevir was evaluated. Combining the inhibitors greatly reduced the frequency with which resistant colonies arose; however, some resistant replicon cells could be isolated by the use of low inhibitor concentrations. These replicons were approximately 1,000-fold less susceptible to HCV-796 and 9-fold less susceptible to boceprevir. They also exhibited resistance to anthranilate nonnucleoside inhibitors of NS5B but were fully sensitive to inhibitors of different mechanisms: a pyranoindole, Hsp90 inhibitors, an NS5B nucleoside inhibitor, and pegylated interferon (Peg-IFN). The replicon was cleared from the combination-resistant cells by extended treatment with Peg-IFN. Mutations known to confer resistance to HCV-796 (NS5B C316Y) and boceprevir (NS3 V170A) were present in the combination-resistant replicons. These changes could be selected together and coexist in the same genome. The replicon bearing both changes exhibited reduced sensitivity to inhibition by HCV-796 and boceprevir but had a reduced replicative capacity.
|
Antiviral activity against Hepatitis C virus genotype 1b Con1 harboring C316Y and C445F mutations mutant infected in human HuH7.5 cells after 72 hrs by gaussia luciferase reporter assay
|
Hepatitis C virus
|
821.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Selection and characterization of hepatitis C virus replicons dually resistant to the polymerase and protease inhibitors HCV-796 and boceprevir (SCH 503034).
Year : 2009
Volume : 53
Issue : 2
First Page : 401
Last Page : 411
Authors : Flint M, Mullen S, Deatly AM, Chen W, Miller LZ, Ralston R, Broom C, Emini EA, Howe AY.
Abstract : HCV-796 is a nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) polymerase, and boceprevir is an inhibitor of the NS3 serine protease. The emergence of replicon variants resistant to the combination of HCV-796 and boceprevir was evaluated. Combining the inhibitors greatly reduced the frequency with which resistant colonies arose; however, some resistant replicon cells could be isolated by the use of low inhibitor concentrations. These replicons were approximately 1,000-fold less susceptible to HCV-796 and 9-fold less susceptible to boceprevir. They also exhibited resistance to anthranilate nonnucleoside inhibitors of NS5B but were fully sensitive to inhibitors of different mechanisms: a pyranoindole, Hsp90 inhibitors, an NS5B nucleoside inhibitor, and pegylated interferon (Peg-IFN). The replicon was cleared from the combination-resistant cells by extended treatment with Peg-IFN. Mutations known to confer resistance to HCV-796 (NS5B C316Y) and boceprevir (NS3 V170A) were present in the combination-resistant replicons. These changes could be selected together and coexist in the same genome. The replicon bearing both changes exhibited reduced sensitivity to inhibition by HCV-796 and boceprevir but had a reduced replicative capacity.
|
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
|
275.8
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
|
201.2
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
|
91.5
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 D168V mutant by transient replicon assay
|
Hepatitis C virus subtype 1b
|
40.0
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
|
400.0
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 Hepatitis C virus subtype 1b harboring protease R155K mutant by transient replicon assay
|
Hepatitis C virus subtype 1b
|
700.0
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 Hepatitis C virus subtype 2a J6/JFH transfected in human Huh7.5 cells assessed as inhibition of viral replication after 48 hrs by luciferase reporter gene assay
|
Hepatitis C virus subtype 2a
|
800.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Analogs design, synthesis and biological evaluation of peptidomimetics with potential anti-HCV activity.
Year : 2013
Volume : 21
Issue : 10
First Page : 2742
Last Page : 2755
Authors : Lasheen DS, Ismail MA, Abou El Ella DA, Ismail NS, Eid S, Vleck S, Glenn JS, Watts AG, Abouzid KA.
Abstract : Two series of peptidomimetics were designed, prepared and evaluated for their anti-HCV activity. One series possesses a C-terminal carboxylate functionality. In the other series, the electrophilic vinyl sulfonate moiety was introduced as a novel class of HCV NS3/4A protease inhibitors. In vitro based studies were then performed to evaluate the efficacies of the inhibitors using Human hepatoma cells, with the vinyl sulfonate ester (10) in particular, found to have highly potent anti-HCV activity with an EC(50) = 0.296 μM. Finally, molecular modeling studies were performed through docking of the synthesized compounds in the HCV NS3/4A protease active site to assess their binding modes with the enzyme and gain further insight into their structure-activity relationships.
|
Inhibition of Hepatitis C virus genotype 1b NS3/4A protease V170A mutant
|
Hepatitis C virus subtype 1b
|
770.0
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
|
350.0
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 D168V mutant
|
Hepatitis C virus subtype 1b
|
220.0
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 D168A mutant
|
Hepatitis C virus subtype 1b
|
520.0
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
|
520.0
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).
|
Antiviral activity against Hepatitis C virus infected in human HuH7 cells assessed as viral RNA replication
|
Hepatitis C virus
|
10.0
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 3a full-length NS3 protease assessed as overall/observed affinity by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 3a
|
3.9
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
Inhibition of Hepatitis C virus genotype 1b full-length NS3/NS4A protease assessed as overall/observed affinity by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 1b
|
38.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
Inhibition of Hepatitis C virus genotype 1b full-length NS3 protease assessed as overall/observed affinity by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 1b
|
90.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
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
|
14.0
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 genotype 1a
|
Hepatitis C virus subtype 1a
|
200.0
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.
|
Drug metabolism in human liver cytosol treated with 20 uM [14C]boceprevir assessed as 2 uM AKR inhibitor ritonavir-mediated metabolite formation after 60 mins co-incubated and pre-incubated with ritonavir by LC-MS/MS/FSA method
|
Homo sapiens
|
0.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Characterization of human liver enzymes involved in the biotransformation of boceprevir, a hepatitis C virus protease inhibitor.
Year : 2011
Volume : 39
Issue : 3
First Page : 510
Last Page : 521
Authors : Ghosal A, Yuan Y, Tong W, Su AD, Gu C, Chowdhury SK, Kishnani NS, Alton KB.
Abstract : Boceprevir (SCH 503034), a protease inhibitor, is under clinical development for the treatment of human hepatitis C virus infections. In human liver microsomes, formation of oxidative metabolites after incubations with [(14)C]boceprevir was catalyzed by CYP3A4 and CYP3A5. In addition, the highest turnover was observed in recombinant CYP3A4 and CYP3A5. After a single radiolabeled dose to human, boceprevir was subjected to two distinct pathways, namely cytochrome P450-mediated oxidation and ketone reduction. Therefore, attempts were made to identify the enzymes responsible for the formation of carbonyl-reduced metabolites. Human liver S9 and cytosol converted ∼ 28 and ∼ 68% of boceprevir to M28, respectively, in the presence of an NADPH-generating system. Screening of boceprevir with recombinant human aldo-keto reductases (AKRs) revealed that AKR1C2 and AKR1C3 exhibited catalytic activity with respect to the formation of M+2 metabolites (M28 and M31). The formation of M28 was inhibited by 100 μM flufenamic acid (80.3%), 200 μM mefenamic acid (83.7%), and 100 μM phenolphthalein (86.1%), known inhibitors of AKRs, suggesting its formation through carbonyl reduction pathway. Formation of M28 was also inhibited by 100 μM diazepam (75.1%), 1 mM ibuprofen (70%), and 200 μM diflunisal (89.4%). These data demonstrated that CYP3A4 and CYP3A5 are primarily responsible for the formation of oxidative metabolites and the formation of M28 and M31, the keto-reduced metabolites, are most likely mediated by AKR1C2 and AKR1C3. Because the biotransformation and clearance of boceprevir involves two different enzymatic pathways, boceprevir is less likely to be a victim of significant drug-drug interaction with concomitant medication affecting either of these pathways.
|
Drug metabolism in human liver cytosol treated with 20 uM [14C]boceprevir assessed as 2 uM AKR inhibitor ketoconazole-mediated metabolite formation after 60 mins by LC-MS/MS/FSA method
|
Homo sapiens
|
0.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Characterization of human liver enzymes involved in the biotransformation of boceprevir, a hepatitis C virus protease inhibitor.
Year : 2011
Volume : 39
Issue : 3
First Page : 510
Last Page : 521
Authors : Ghosal A, Yuan Y, Tong W, Su AD, Gu C, Chowdhury SK, Kishnani NS, Alton KB.
Abstract : Boceprevir (SCH 503034), a protease inhibitor, is under clinical development for the treatment of human hepatitis C virus infections. In human liver microsomes, formation of oxidative metabolites after incubations with [(14)C]boceprevir was catalyzed by CYP3A4 and CYP3A5. In addition, the highest turnover was observed in recombinant CYP3A4 and CYP3A5. After a single radiolabeled dose to human, boceprevir was subjected to two distinct pathways, namely cytochrome P450-mediated oxidation and ketone reduction. Therefore, attempts were made to identify the enzymes responsible for the formation of carbonyl-reduced metabolites. Human liver S9 and cytosol converted ∼ 28 and ∼ 68% of boceprevir to M28, respectively, in the presence of an NADPH-generating system. Screening of boceprevir with recombinant human aldo-keto reductases (AKRs) revealed that AKR1C2 and AKR1C3 exhibited catalytic activity with respect to the formation of M+2 metabolites (M28 and M31). The formation of M28 was inhibited by 100 μM flufenamic acid (80.3%), 200 μM mefenamic acid (83.7%), and 100 μM phenolphthalein (86.1%), known inhibitors of AKRs, suggesting its formation through carbonyl reduction pathway. Formation of M28 was also inhibited by 100 μM diazepam (75.1%), 1 mM ibuprofen (70%), and 200 μM diflunisal (89.4%). These data demonstrated that CYP3A4 and CYP3A5 are primarily responsible for the formation of oxidative metabolites and the formation of M28 and M31, the keto-reduced metabolites, are most likely mediated by AKR1C2 and AKR1C3. Because the biotransformation and clearance of boceprevir involves two different enzymatic pathways, boceprevir is less likely to be a victim of significant drug-drug interaction with concomitant medication affecting either of these pathways.
|
Drug metabolism in human liver cytosol treated with 20 uM [14C]boceprevir assessed as 200 uM AKR inhibitor diflunisal-mediated metabolite formation after 60 mins by LC-MS/MS/FSA method
|
Homo sapiens
|
89.4
%
|
|
Journal : Drug Metab. Dispos.
Title : Characterization of human liver enzymes involved in the biotransformation of boceprevir, a hepatitis C virus protease inhibitor.
Year : 2011
Volume : 39
Issue : 3
First Page : 510
Last Page : 521
Authors : Ghosal A, Yuan Y, Tong W, Su AD, Gu C, Chowdhury SK, Kishnani NS, Alton KB.
Abstract : Boceprevir (SCH 503034), a protease inhibitor, is under clinical development for the treatment of human hepatitis C virus infections. In human liver microsomes, formation of oxidative metabolites after incubations with [(14)C]boceprevir was catalyzed by CYP3A4 and CYP3A5. In addition, the highest turnover was observed in recombinant CYP3A4 and CYP3A5. After a single radiolabeled dose to human, boceprevir was subjected to two distinct pathways, namely cytochrome P450-mediated oxidation and ketone reduction. Therefore, attempts were made to identify the enzymes responsible for the formation of carbonyl-reduced metabolites. Human liver S9 and cytosol converted ∼ 28 and ∼ 68% of boceprevir to M28, respectively, in the presence of an NADPH-generating system. Screening of boceprevir with recombinant human aldo-keto reductases (AKRs) revealed that AKR1C2 and AKR1C3 exhibited catalytic activity with respect to the formation of M+2 metabolites (M28 and M31). The formation of M28 was inhibited by 100 μM flufenamic acid (80.3%), 200 μM mefenamic acid (83.7%), and 100 μM phenolphthalein (86.1%), known inhibitors of AKRs, suggesting its formation through carbonyl reduction pathway. Formation of M28 was also inhibited by 100 μM diazepam (75.1%), 1 mM ibuprofen (70%), and 200 μM diflunisal (89.4%). These data demonstrated that CYP3A4 and CYP3A5 are primarily responsible for the formation of oxidative metabolites and the formation of M28 and M31, the keto-reduced metabolites, are most likely mediated by AKR1C2 and AKR1C3. Because the biotransformation and clearance of boceprevir involves two different enzymatic pathways, boceprevir is less likely to be a victim of significant drug-drug interaction with concomitant medication affecting either of these pathways.
|
Drug metabolism in human liver cytosol treated with 20 uM [14C]boceprevir assessed as 1000 uM AKR inhibitor ibuprofen-mediated metabolite formation after 60 mins by LC-MS/MS/FSA method
|
Homo sapiens
|
70.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Characterization of human liver enzymes involved in the biotransformation of boceprevir, a hepatitis C virus protease inhibitor.
Year : 2011
Volume : 39
Issue : 3
First Page : 510
Last Page : 521
Authors : Ghosal A, Yuan Y, Tong W, Su AD, Gu C, Chowdhury SK, Kishnani NS, Alton KB.
Abstract : Boceprevir (SCH 503034), a protease inhibitor, is under clinical development for the treatment of human hepatitis C virus infections. In human liver microsomes, formation of oxidative metabolites after incubations with [(14)C]boceprevir was catalyzed by CYP3A4 and CYP3A5. In addition, the highest turnover was observed in recombinant CYP3A4 and CYP3A5. After a single radiolabeled dose to human, boceprevir was subjected to two distinct pathways, namely cytochrome P450-mediated oxidation and ketone reduction. Therefore, attempts were made to identify the enzymes responsible for the formation of carbonyl-reduced metabolites. Human liver S9 and cytosol converted ∼ 28 and ∼ 68% of boceprevir to M28, respectively, in the presence of an NADPH-generating system. Screening of boceprevir with recombinant human aldo-keto reductases (AKRs) revealed that AKR1C2 and AKR1C3 exhibited catalytic activity with respect to the formation of M+2 metabolites (M28 and M31). The formation of M28 was inhibited by 100 μM flufenamic acid (80.3%), 200 μM mefenamic acid (83.7%), and 100 μM phenolphthalein (86.1%), known inhibitors of AKRs, suggesting its formation through carbonyl reduction pathway. Formation of M28 was also inhibited by 100 μM diazepam (75.1%), 1 mM ibuprofen (70%), and 200 μM diflunisal (89.4%). These data demonstrated that CYP3A4 and CYP3A5 are primarily responsible for the formation of oxidative metabolites and the formation of M28 and M31, the keto-reduced metabolites, are most likely mediated by AKR1C2 and AKR1C3. Because the biotransformation and clearance of boceprevir involves two different enzymatic pathways, boceprevir is less likely to be a victim of significant drug-drug interaction with concomitant medication affecting either of these pathways.
|
Drug metabolism in human liver cytosol treated with 20 uM [14C]boceprevir assessed as 100 uM AKR inhibitor diazepam-mediated metabolite formation after 60 mins by LC-MS/MS/FSA method
|
Homo sapiens
|
75.1
%
|
|
Journal : Drug Metab. Dispos.
Title : Characterization of human liver enzymes involved in the biotransformation of boceprevir, a hepatitis C virus protease inhibitor.
Year : 2011
Volume : 39
Issue : 3
First Page : 510
Last Page : 521
Authors : Ghosal A, Yuan Y, Tong W, Su AD, Gu C, Chowdhury SK, Kishnani NS, Alton KB.
Abstract : Boceprevir (SCH 503034), a protease inhibitor, is under clinical development for the treatment of human hepatitis C virus infections. In human liver microsomes, formation of oxidative metabolites after incubations with [(14)C]boceprevir was catalyzed by CYP3A4 and CYP3A5. In addition, the highest turnover was observed in recombinant CYP3A4 and CYP3A5. After a single radiolabeled dose to human, boceprevir was subjected to two distinct pathways, namely cytochrome P450-mediated oxidation and ketone reduction. Therefore, attempts were made to identify the enzymes responsible for the formation of carbonyl-reduced metabolites. Human liver S9 and cytosol converted ∼ 28 and ∼ 68% of boceprevir to M28, respectively, in the presence of an NADPH-generating system. Screening of boceprevir with recombinant human aldo-keto reductases (AKRs) revealed that AKR1C2 and AKR1C3 exhibited catalytic activity with respect to the formation of M+2 metabolites (M28 and M31). The formation of M28 was inhibited by 100 μM flufenamic acid (80.3%), 200 μM mefenamic acid (83.7%), and 100 μM phenolphthalein (86.1%), known inhibitors of AKRs, suggesting its formation through carbonyl reduction pathway. Formation of M28 was also inhibited by 100 μM diazepam (75.1%), 1 mM ibuprofen (70%), and 200 μM diflunisal (89.4%). These data demonstrated that CYP3A4 and CYP3A5 are primarily responsible for the formation of oxidative metabolites and the formation of M28 and M31, the keto-reduced metabolites, are most likely mediated by AKR1C2 and AKR1C3. Because the biotransformation and clearance of boceprevir involves two different enzymatic pathways, boceprevir is less likely to be a victim of significant drug-drug interaction with concomitant medication affecting either of these pathways.
|
Inhibition of HCV NS3/4A protease
|
Hepatitis C virus
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : A Journey around the Medicinal Chemistry of Hepatitis C Virus Inhibitors Targeting NS4B: From Target to Preclinical Drug Candidates.
Year : 2016
Volume : 59
Issue : 1
First Page : 16
Last Page : 41
Authors : Cannalire R, Barreca ML, Manfroni G, Cecchetti V.
Abstract : Hepatitis C virus (HCV) infection is a global health burden with an estimated 130-170 million chronically infected individuals and is the cause of serious liver diseases such as cirrhosis and hepatocellular carcinoma. HCV NS4B protein represents a validated target for the identification of new drugs to be added to the combination regimen recently approved. During the last years, NS4B has thus been the object of impressive medicinal chemistry efforts, which led to the identification of promising preclinical candidates. In this context, the present review aims to discuss research published on NS4B functional inhibitors focusing the attention on hit identification, hit-to-lead optimization, ADME profile evaluation, and the structure-activity relationship data raised for each compound family taken into account. The information delivered in this review will be a useful and valuable tool for those medicinal chemists dealing with research programs focused on NS4B and aimed at the identification of innovative anti-HCV compounds.
|
Antiviral activity against HCV genotype 1b
|
Hepatitis C virus subtype 1b
|
350.0
nM
|
|
Journal : J. Med. Chem.
Title : A Journey around the Medicinal Chemistry of Hepatitis C Virus Inhibitors Targeting NS4B: From Target to Preclinical Drug Candidates.
Year : 2016
Volume : 59
Issue : 1
First Page : 16
Last Page : 41
Authors : Cannalire R, Barreca ML, Manfroni G, Cecchetti V.
Abstract : Hepatitis C virus (HCV) infection is a global health burden with an estimated 130-170 million chronically infected individuals and is the cause of serious liver diseases such as cirrhosis and hepatocellular carcinoma. HCV NS4B protein represents a validated target for the identification of new drugs to be added to the combination regimen recently approved. During the last years, NS4B has thus been the object of impressive medicinal chemistry efforts, which led to the identification of promising preclinical candidates. In this context, the present review aims to discuss research published on NS4B functional inhibitors focusing the attention on hit identification, hit-to-lead optimization, ADME profile evaluation, and the structure-activity relationship data raised for each compound family taken into account. The information delivered in this review will be a useful and valuable tool for those medicinal chemists dealing with research programs focused on NS4B and aimed at the identification of innovative anti-HCV compounds.
|
Inhibition of HCV NS3/4A protease using AcDTEDVVP(Nva)-O-PAP as substrate pretreated with substrate for 3 mins followed by enzyme addition measured after 60 mins by spectrophotometric method
|
Hepatitis C virus
|
14.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : QSAR studies of the bioactivity of hepatitis C virus (HCV) NS3/4A protease inhibitors by multiple linear regression (MLR) and support vector machine (SVM).
Year : 2017
Volume : 27
Issue : 13
First Page : 2931
Last Page : 2938
Authors : Qin Z, Wang M, Yan A.
Abstract : In this study, quantitative structure-activity relationship (QSAR) models using various descriptor sets and training/test set selection methods were explored to predict the bioactivity of hepatitis C virus (HCV) NS3/4A protease inhibitors by using a multiple linear regression (MLR) and a support vector machine (SVM) method. 512 HCV NS3/4A protease inhibitors and their IC50 values which were determined by the same FRET assay were collected from the reported literature to build a dataset. All the inhibitors were represented with selected nine global and 12 2D property-weighted autocorrelation descriptors calculated from the program CORINA Symphony. The dataset was divided into a training set and a test set by a random and a Kohonen's self-organizing map (SOM) method. The correlation coefficients (r2) of training sets and test sets were 0.75 and 0.72 for the best MLR model, 0.87 and 0.85 for the best SVM model, respectively. In addition, a series of sub-dataset models were also developed. The performances of all the best sub-dataset models were better than those of the whole dataset models. We believe that the combination of the best sub- and whole dataset SVM models can be used as reliable lead designing tools for new NS3/4A protease inhibitors scaffolds in a drug discovery pipeline.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
13.18
%
|
|
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.
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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
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Chlorocebus sabaeus
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-0.02
%
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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
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Chlorocebus sabaeus
|
-0.02
%
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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.
