The treatment of chronic hepatitis C virus (HCV) infection is undergoing a radical transformation through the introduction of direct-acting antiviral agents (DAAs).  Recent clinical data indicate DAA combinations offer the prospect of curing HCV infection with interferon-free, all-oral regimens with reduced treatment durations.  Results of clinical trials with filibuvir and, more recently, VX-222 have demonstrated the value of inhibiting HCV replication via binding to the thumb site II region of the viral polymerase NS5B. Herein we describe the medicinal chemistry analysis of ligands binding to this site and the execution of a project that culminated in the identification of GS-9669, a novel thumb site II inhibitor with improved in vitro potency against both wild-type virus and several known resistance mutants.  The structure of GS-9669 will be disclosed, and clinical antiviral and pharmacokinetic data will also be reviewed.

Discovery of GS-9669, a thumb site II non-nucleoside inhibitor of NS5B for the treatment of genotype 1 chronic hepatitis C infection

244th National Meeting (2012)

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