HCV NS5b RNA-dependent RNA polymerase inhibitors: from alpha,gamma-diketoacids to 4,5-dihydroxypyrimidine- or 3-methyl-5-hydroxypyrimidinonecarboxylic acids. Design and synthesis

J Med Chem. 2004 Oct 21;47(22):5336-9. doi: 10.1021/jm0494669.


A new class of the HCV NS5b RNA-dependent RNA polymerase inhibitors, the dihyroxypyrimidinecarboxylic acid derivative, was designed from a diketoacid and meconic acid derivative discovered by screening. Mechanism of action and essential moieties required for activity were identified. The corresponding N-methylpyrimidinone was also prepared; both classes are novel, reversible, and selective inhibitors of the HCV NS5b polymerase with improved druglike characteristics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Drug Design
  • Hepacivirus / enzymology
  • In Vitro Techniques
  • Isomerism
  • Keto Acids / chemical synthesis*
  • Keto Acids / chemistry
  • Keto Acids / pharmacology
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • RNA-Dependent RNA Polymerase / chemistry
  • Rats
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / metabolism*


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