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

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.

1216 IN VITRO INHIBITION OF HEPATIC BILIRUBIN TRANSPORTERS BY THE HCV NS3 PROTEASE INHIBITOR GS-9451 AND IN VIVO CORRELATION IN HEALTHY SUBJECTS

2012 ◽  
Vol 56 ◽  
pp. S482-S483
Author(s):  
J.C. Yang ◽  
C. Yang ◽  
A. Mathias ◽  
L. Moorehead ◽  
D. Brainard ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Healthy Subjects ◽  
In Vitro Inhibition ◽  
Ns3 Protease

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 brivanib (BMS-540215), a potent VEGFR2 inhibitor and its alanine ester prodrug brivanib alaninate

2009 ◽  
Vol 65 (1) ◽  
pp. 55-66 ◽  
Author(s):  
Punit H. Marathe ◽  
Amrita V. Kamath ◽  
Yueping Zhang ◽  
Celia D’Arienzo ◽  
Rajeev Bhide ◽  
...  
Keyword(s):  
In Vitro Metabolism ◽  
Preclinical Pharmacokinetics ◽  
Brivanib Alaninate ◽  
Ester Prodrug

Preclinical Pharmacokinetics and In Vitro Metabolism of BMS-690514, a Potent Inhibitor of EGFR and VEGFR2

2010 ◽  
Vol 99 (8) ◽  
pp. 3579-3593 ◽  
Author(s):  
Punit Marathe ◽  
Yuwei Tang ◽  
Bogdan Sleczka ◽  
David Rodrigues ◽  
Ashvinikumar Gavai ◽  
...  
Keyword(s):  
Potent Inhibitor ◽  
In Vitro Metabolism ◽  
Preclinical Pharmacokinetics
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