Synthesis and biological evaluation of new potent and selective HCV NS5A inhibitors

  • Bioorg Med Chem Lett. 2012 May 15;22(10):3488-91. doi: 10.1016/j.bmcl.2012.03.089.
Junxing Shi  1 ,  Longhu Zhou ,  Franck Amblard ,  Drew R Bobeck ,  Hongwang Zhang ,  Peng Liu ,  Lavanya Bondada ,  Tamara R McBrayer ,  Phillip M Tharnish ,  Tony Whitaker ,  Steven J Coats ,  Raymond F Schinazi
Affiliations
  • 1. RFS Pharma, LLC, 1860 Montreal Road, Tucker, GA 30084, USA.
PMID: 22507961 DOI: 10.1016/j.bmcl.2012.03.089
Abstract

NS5A inhibitors are a new class of direct-acting Antiviral agents which display very potent anti-HCV activity in vitro and in humans. Rationally designed modifications to the central biphenyl linkage of a known NS5A series led to selection of several compounds that were synthesized and evaluated in a HCV genotype 1b replicon. The straight triphenyl linked compound 11a showed similar anti-HCV activity to the clinical compound BMS-790052 and a superior cytotoxicity profile in three different cell lines, with an EC(50) value of 26 pM and a therapeutic index of over four million in an HCV replicon assay. This triphenyl analog warrants further preclinical evaluation as an anti-HCV agent.