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Preclinical characterization of the novel hepatitis C virus NS3 protease inhibitor GS-9451

Yang, H, Robinson, M, Corsa, AC, Peng, B, Cheng, G, Tian, Y, Wang, Y, Pakdaman, R, Shen, M, Qi, X, Mo, H, Tay, C, Krawczyk, S, Sheng, XC, Kim, CU, Yang, C and Delaney IV, WE (2014) Preclinical characterization of the novel hepatitis C virus NS3 protease inhibitor GS-9451. Antimicrobial Agents and Chemotherapy. pp. 647-653.


GS-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, including in vitro antiviral 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 synergistic in vitro antiviral 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 of in vitro cross-resistance and combination antiviral assays support the ongoing development of GS-9451 in combination with other agents for the treatment of chronic HCV infection. Copyright 2014, American Society for Microbiology. All Rights Reserved

Item Type: Article
Additional Information: NIBR author: Robinson, M institute: NIBR- address only contributor address: (Yang, Robinson, Corsa, Peng, Cheng, Tian, Wang, Pakdaman, Shen, Qi, Mo, Tay, Krawczyk, Sheng, Kim, Yang, Delaney IV) Gilead Sciences, Foster City, CA, United States (Robinson) Novartis Institute for Biomedical Research, Emeryville, CA, United States (Sheng) Accelas Pharmaceutical Co., Qixia District, Nanjing, Jiangsu, China
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12


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