Discovery of a potent boronic acid derived inhibitor of the HCV RNA-dependent RNA polymerase

  • J Med Chem. 2014 Mar 13;57(5):1902-13. doi: 10.1021/jm400317w.
Andrew Maynard  1 ,  Renae M Crosby ,  Byron Ellis ,  Robert Hamatake ,  Zhi Hong ,  Brian A Johns ,  Kirsten M Kahler ,  Cecilia Koble ,  Anna Leivers ,  Martin R Leivers ,  Amanda Mathis ,  Andrew J Peat ,  Jeffrey J Pouliot ,  Christopher D Roberts ,  Vicente Samano ,  Rachel M Schmidt ,  Gary K Smith ,  Andrew Spaltenstein ,  Eugene L Stewart ,  Pia Thommes ,  Elizabeth M Turner ,  Christian Voitenleitner ,  Jill T Walker ,  Greg Waitt ,  Jason Weatherhead ,  Kurt Weaver ,  Shawn Williams ,  Lois Wright ,  Zhiping Z Xiong ,  David Haigh ,  J Brad Shotwell
Affiliations
  • 1. GlaxoSmithKline, Infectious Diseases Medicines Discovery Unit, 5 Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States.
PMID: 23672667 DOI: 10.1021/jm400317w
Abstract

A boronic acid moiety was found to be a critical pharmacophore for enhanced in vitro potency against wild-type hepatitis C replicons and known clinical polymorphic and resistant HCV mutant replicons. The synthesis, optimization, and structure-activity relationships associated with inhibition of HCV replication in a subgenomic replication system for a series of non-nucleoside boron-containing HCV RNA-dependent RNA polymerase (NS5B) inhibitors are described. A summary of the discovery of 3 (GSK5852), a molecule which entered clinical trials in subjects infected with HCV in 2011, is included.

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