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

  • Yang, Huiling
  • Robinson, Margaret
  • Corsa, Amoreena C
  • Peng, Betty
  • Cheng, Guofeng
  • Tian, Yang
  • Wang, Yujin
  • Pakdaman, Rowchanak
  • Shen, Marian
  • Qi, Xiaoping
  • Mo, Hongmei
  • Tay, Chin
  • Krawczyk, Steve
  • Sheng, X Christopher
  • Kim, Choung U
  • Yang, Chris
  • Delaney, William E 4th
Published Article
Antimicrobial Agents and Chemotherapy
American Society for Microbiology
Publication Date
Jan 01, 2014
DOI: 10.1128/AAC.00487-13
PMID: 23939899


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.

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