Discovery of alpha,gamma-diketo acids as potent selective and reversible inhibitors of hepatitis C virus NS5b RNA-dependent RNA polymerase

J Med Chem. 2004 Jan 1;47(1):14-7. doi: 10.1021/jm0342109.

Abstract

alpha,gamma-Diketo acids (DKA) were discovered from screening as selective and reversible inhibitors of hepatitis C virus NS5b RNA-dependent RNA polymerase. The diketo acid moiety proved essential for activity, while substitution on the gamma position was necessary for selectivity and potency. Optimization led to the identification of a DKA inhibitor of NS5b polymerase with IC(50) = 45 nM, one of the most potent HCV NS5b polymerase inhibitors reported.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Keto Acids / chemical synthesis*
  • Keto Acids / chemistry
  • Models, Molecular
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • RNA-Dependent RNA Polymerase / chemistry
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / physiology*

Substances

  • Keto Acids
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus
  • RNA-Dependent RNA Polymerase