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. Epub 2012 Mar 29.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacology*
  • Cell Line
  • Hepacivirus / drug effects*
  • Humans
  • Microbial Sensitivity Tests
  • Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

  • Antiviral Agents
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus