Discovery of the first C-nucleoside HCV polymerase inhibitor (GS-6620) with demonstrated antiviral response in HCV infected patients

  • J Med Chem. 2014 Mar 13;57(5):1812-25. doi: 10.1021/jm400201a.
Aesop Cho  1 ,  Lijun Zhang ,  Jie Xu ,  Rick Lee ,  Thomas Butler ,  Sammy Metobo ,  Vangelis Aktoudianakis ,  Willard Lew ,  Hong Ye ,  Michael Clarke ,  Edward Doerffler ,  Daniel Byun ,  Ting Wang ,  Darius Babusis ,  Anne C Carey ,  Polina German ,  Dorothea Sauer ,  Weidong Zhong ,  Stephen Rossi ,  Martijn Fenaux ,  John G McHutchison ,  Jason Perry ,  Joy Feng ,  Adrian S Ray ,  Choung U Kim
Affiliations
  • 1. Gilead Sciences, 333 Lakeside Drive, Foster City, California 94044, United States.
PMID: 23547794 DOI: 10.1021/jm400201a
Abstract

Hepatitis C virus (HCV) Infection presents an unmet medical need requiring more effective treatment options. Nucleoside inhibitors (NI) of HCV polymerase (NS5B) have demonstrated pan-genotypic activity and durable Antiviral response in the clinic, and they are likely to become a key component of future treatment regimens. NI candidates that have entered clinical development thus far have all been N-nucleoside derivatives. Herein, we report the discovery of a C-nucleoside class of NS5B inhibitors. Exploration of adenosine analogs in this class identified 1'-cyano-2'-C-methyl 4-aza-7,9-dideaza adenosine as a potent and selective inhibitor of NS5B. A monophosphate prodrug approach afforded a series of compounds showing submicromolar activity in HCV replicon assays. Further pharmacokinetic optimization for sufficient oral absorption and liver triphosphate loading led to identification of a clinical development candidate GS-6620. In a phase I clinical study, the potential for potent activity was demonstrated but with high intra- and interpatient pharmacokinetic and pharmacodynamic variability.

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