Inhibitors of hepatitis C virus polymerase: synthesis and characterization of novel 2-oxy-6-fluoro-N-((S)-1-hydroxy-3-phenylpropan-2-yl)-benzamides

Bioorg Med Chem Lett. 2010 Apr 1;20(7):2119-24. doi: 10.1016/j.bmcl.2010.02.054. Epub 2010 Feb 18.

Abstract

SAR exploration from an initial hit, (S)-N-(2-cyclohexenylethyl)-2-fluoro-6-(2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoethoxy)benzamide (1), identified using our proprietary automated ligand identification system (ALIS),(1) has led to a novel series of selective hepatitis C virus (HCV) NS5B polymerase inhibitors with improved in vitro potency as exemplified by (S)-2-fluoro-6-(2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoethoxy)-N-isopentyl-N-methylbenzamidecarboxamide (41) (IC(50)=0.5 microM). The crystal structure of an analogue (44) was solved and provided rationalization of the SAR of this series, which binds in a distinct manner in the palm domain of NS5B, consistent with biochemical analysis using enzyme mutant variants. These data warrant further lead optimization efforts on this novel series of non-nucleoside inhibitors targeting the HCV polymerase.

MeSH terms

  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Benzamides / chemistry*
  • Benzamides / pharmacology*
  • Crystallography
  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Hepacivirus / enzymology*
  • Hepatitis C / drug therapy
  • Humans
  • Models, Molecular
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors
  • RNA-Dependent RNA Polymerase / chemistry
  • RNA-Dependent RNA Polymerase / metabolism
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / chemistry
  • Viral Nonstructural Proteins / metabolism*

Substances

  • Antiviral Agents
  • Benzamides
  • Enzyme Inhibitors
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus
  • RNA-Dependent RNA Polymerase