Discovery and initial optimization of alkoxyanthranilic acid derivatives as inhibitors of HCV NS5B polymerase

Bioorg Med Chem Lett. 2017 Jan 15;27(2):295-298. doi: 10.1016/j.bmcl.2016.11.054. Epub 2016 Nov 22.

Abstract

Alkoxyanthranilic acid derivatives have been identified to inhibit HCV NS5B polymerase, binding in an allosteric site located at the convergence of the palm and thumb regions. Information from co-crystal structures guided the structural design strategy. Ultimately, two independent structural modifications led to a similar shift in binding mode that when combined led to a synergistic improvement in potency and the identification of inhibitors with sub-micromolar HCV NS5B binding potency.

Keywords: Allosteric inhibitors; Hepatitis C virus (HCV); NS5B polymerase; Primer grip.

MeSH terms

  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / metabolism
  • ortho-Aminobenzoates / chemical synthesis
  • ortho-Aminobenzoates / chemistry
  • ortho-Aminobenzoates / pharmacology*

Substances

  • Enzyme Inhibitors
  • Viral Nonstructural Proteins
  • ortho-Aminobenzoates
  • anthranilic acid
  • NS-5 protein, hepatitis C virus