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

Yang, H and Robinson, M and Corsa, AC and Peng, B and Cheng, G and Tian, Y and Wang, Y and Pakdaman, R and Shen, M and Qi, X and Mo, H and Tay, C and Krawczyk, S and Sheng, XC and Kim, CU and 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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