Preclinical Pharmacokinetics and In Vitro Metabolism of Asunaprevir (BMS-650032), a Potent Hepatitis C Virus NS3 Protease Inhibitor

2015 ◽  
Vol 104 (9) ◽  
pp. 2813-2823 ◽  
Author(s):  
Kathleen W. Mosure ◽  
Jay O. Knipe ◽  
Marc Browning ◽  
Vinod Arora ◽  
Yue-Zhong Shu ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitor ◽  
In Vitro Metabolism ◽  
Preclinical Pharmacokinetics ◽  
Ns3 Protease

scholarly journals Preclinical Characterization of the Novel Hepatitis C Virus NS3 Protease Inhibitor GS-9451

2013 ◽  
Vol 58 (2) ◽  
pp. 647-653 ◽  
Author(s):  
Huiling Yang ◽  
Margaret Robinson ◽  
Amoreena C. Corsa ◽  
Betty Peng ◽  
Guofeng Cheng ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Protease Inhibitor ◽  
Hcv Infection ◽  
Cross Resistance ◽  
Protease Gene ◽  
Ns5a Inhibitor ◽  
Ns3 Protease

ABSTRACTGS-9451 is a selective hepatitis C virus (HCV) NS3 protease inhibitor in development for the treatment of genotype 1 (GT1) HCV infection. Key preclinical properties of GS-9451, includingin vitroantiviral activity, selectivity, cross-resistance, and combination activity, as well as pharmacokinetic properties, were determined. In multiple GT1a and GT1b replicon cell lines, GS-9451 had mean 50% effective concentrations (EC50s) of 13 and 5.4 nM, respectively, with minimal cytotoxicity; similar potency was observed in chimeric replicons encoding the NS3 protease gene of GT1 clinical isolates. GS-9451 was less active in GT2a replicon cells (EC50= 316 nM). Additive to synergisticin vitroantiviral activity was observed when GS-9451 was combined with other agents, including alpha interferon, ribavirin, and the polymerase inhibitors GS-6620 and tegobuvir (GS-9190), as well as the NS5A inhibitor ledipasvir (GS-5885). GS-9451 retained wild-type activity against multiple classes of NS5B and NS5A inhibitor resistance mutations. GS-9451 was stable in hepatic microsomes and hepatocytes from human and three other tested species. Systemic clearance was low in dogs and monkeys but high in rats. GS-9451 showed good oral bioavailability in all three species tested. In rats, GS-9451 levels were ∼40-fold higher in liver than plasma after intravenous dosing, and elimination of GS-9451 was primarily through biliary excretion. Together, these results are consistent with the antiviral activity observed in a recent phase 1b study. The results ofin vitrocross-resistance and combination antiviral assays support the ongoing development of GS-9451 in combination with other agents for the treatment of chronic HCV infection.

scholarly journals In VitroResistance Profile of the Hepatitis C Virus NS3 Protease Inhibitor BI 201335

2011 ◽  
Vol 56 (1) ◽  
pp. 569-572 ◽  
Author(s):  
Lisette Lagacé ◽  
Peter W. White ◽  
Christiane Bousquet ◽  
Nathalie Dansereau ◽  
Florence Dô ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Alpha Interferon ◽  
Phenotypic Characterization ◽  
Genotype 1A ◽  
Ns3 Protease

ABSTRACTThein vitroresistance profile of BI 201335 was evaluated through selection and characterization of variants in genotype 1a (GT 1a) and genotype 1b (GT 1b) replicons. NS3 R155K and D168V were the most frequently observed resistant variants. Phenotypic characterization of the mutants revealed shifts in sensitivity specific to BI 201335 that did not alter susceptibility to alpha interferon. In contrast to macrocyclic and covalent protease inhibitors, changes at V36, T54, F43, and Q80 did not confer resistance to BI 201335.

Preclinical Pharmacokinetics and In Vitro Metabolism of BMS-605339: A Novel HCV NS3 Protease Inhibitor

2014 ◽  
Vol 103 (6) ◽  
pp. 1891-1902 ◽  
Author(s):  
Susan Jenkins ◽  
Paul Scola ◽  
Fiona Mcphee ◽  
Jay Knipe ◽  
Christoph Gesenberg ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
In Vitro Metabolism ◽  
Preclinical Pharmacokinetics ◽  
Ns3 Protease

scholarly journals Resistance Analysis of the Hepatitis C Virus NS3 Protease Inhibitor Asunaprevir

2012 ◽  
Vol 56 (7) ◽  
pp. 3670-3681 ◽  
Author(s):  
Fiona McPhee ◽  
Jacques Friborg ◽  
Steven Levine ◽  
Chaoqun Chen ◽  
Paul Falk ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitor ◽  
Clinical Studies ◽  
Replication Capacity ◽  
Replication Complex ◽  
Hcv Genotype ◽  
Genotype 1A ◽  
Genotype 1B ◽  
Ns3 Protease

ABSTRACTAsunaprevir (BMS-650032) is a potent hepatitis C virus (HCV) NS3 protease inhibitor demonstrating efficacy in alfa interferon-sparing, direct-acting antiviral dual-combination regimens (together with the NS5A replication complex inhibitor daclatasvir) in patients chronically infected with HCV genotype 1b. Here, we describe a comprehensivein vitrogenotypic and phenotypic analysis of asunaprevir-associated resistance against genotypes 1a and 1b using HCV replicons and patient samples obtained from clinical studies of short-term asunaprevir monotherapy. During genotype 1a resistance selection using HCV replicons, the primary NS3 protease substitutions identified were R155K, D168G, and I170T, which conferred low- to moderate-level asunaprevir resistance (5- to 21-fold) in transient-transfection susceptibility assays. For genotype 1b, a higher level of asunaprevir-associated resistance was observed at the same selection pressures, ranging from 170- to 400-fold relative to the wild-type control. The primary NS3 protease substitutions identified occurred predominantly at amino acid residue D168 (D168A/G/H/V/Y) and were associated with high-level asunaprevir resistance (16- to 280-fold) and impaired replication capacity. In asunaprevir single-ascending-dose and 3-day multiple-ascending-dose studies in HCV genotype 1a- or 1b-infected patients, the predominant pre-existing NS3 baseline polymorphism was NS3-Q80K. This substitution impacted initial virologic response rates in a single-ascending-dose study, but its effects after multiple doses were more ambiguous. Interestingly, for patient NS3 protease sequences containing Q80 and those containing K80, susceptibilities to asunaprevir were comparable when tested in an enzyme assay. No resistance-associated variants emerged in these clinical studies that significantly impacted susceptibility to asunaprevir. Importantly, asunaprevir-resistant replicons remained susceptible to an NS5A replication complex inhibitor, consistent with a role for asunaprevir in combination therapies.

Inhibition and Binding Kinetics of the Hepatitis C Virus NS3 Protease Inhibitor ITMN-191 Reveals Tight Binding and Slow Dissociative Behavior

Biochemistry ◽  
2009 ◽  
Vol 48 (11) ◽  
pp. 2559-2568 ◽  
Author(s):  
Ravi Rajagopalan ◽  
Shawn Misialek ◽  
Sarah K. Stevens ◽  
David G. Myszka ◽  
Barbara J. Brandhuber ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitor ◽  
Tight Binding ◽  
Binding Kinetics ◽  
Ns3 Protease ◽  
Kinetics Of

scholarly journals Ribavirin Antagonizes the In Vitro Anti-Hepatitis C Virus Activity of 2′-C-Methylcytidine, the Active Component of Valopicitabine

2006 ◽  
Vol 50 (10) ◽  
pp. 3444-3446 ◽  
Author(s):  
Lotte Coelmont ◽  
Jan Paeshuyse ◽  
Marc P. Windisch ◽  
Erik De Clercq ◽  
Ralf Bartenschlager ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Protease Inhibitor ◽  
Nucleoside Analogue ◽  
Active Component ◽  
Pyrimidine Nucleoside ◽  
Virus Activity ◽  
Hcv Protease

ABSTRACT Ribavirin antagonizes the in vitro anti-hepatitis C virus (HCV) activity of the pyrimidine nucleoside analogue 2′-C-methylcytidine, the active component of the experimental anti-HCV drug valopicitabine. In contrast, the combination of ribavirin with either the purine nucleoside analogue 2′-C-methyladenosine or the HCV protease inhibitor VX-950 resulted in an additive antiviral activity. These findings may have implications when planning clinical studies with valopicitabine.

Interactions of the hepatitis C virus protease inhibitor faldaprevir with cytochrome P450 enzymes: In vitro and in vivo correlation

2015 ◽  
Vol 55 (4) ◽  
pp. 467-477 ◽  
Author(s):  
John P. Sabo ◽  
Jens Kort ◽  
Charles Ballow ◽  
Angela D.M. Kashuba ◽  
Manuel Haschke ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitor ◽  
Cytochrome P450 Enzymes
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