Discoveryof the First C-Nucleoside HCV Polymerase Inhibitor(GS-6620) with Demonstrated Antiviral Response in HCV Infected Patients.

Hepatitis C virus (HCV) infectionpresents an unmet medical need requiring more effective treatmentoptions. Nucleoside inhibitors (NI) of HCV polymerase (NS5B) havedemonstrated pan-genotypic activity and durable antiviral responsein the clinic, and they are likely to become a key component of futuretreatment regimens. NI candidates that have entered clinical developmentthus far have all been N-nucleoside derivatives.Herein, we report the discovery of a C-nucleosideclass of NS5B inhibitors. Exploration of adenosine analogs in thisclass identified 1′-cyano-2′-C-methyl4-aza-7,9-dideaza adenosine as a potent and selective inhibitor ofNS5B. A monophosphate prodrug approach afforded a series of compoundsshowing submicromolar activity in HCV replicon assays. Further pharmacokineticoptimization for sufficient oral absorption and liver triphosphateloading led to identification of a clinical development candidateGS-6620. In a phase I clinical study, the potential for potent activitywas demonstrated but with high intra- and interpatient pharmacokineticand pharmacodynamic variability. [ABSTRACT FROM AUTHOR]