5,6-Dihydro-1H-pyridin-2-ones as potent inhibitors of HCV NS5B polymerase

Bioorg Med Chem Lett. 2009 Jan 15;19(2):451-8. doi: 10.1016/j.bmcl.2008.11.048. Epub 2008 Nov 18.

Abstract

5,6-Dihydro-1H-pyridin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4ad displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; IC(50) (1a)<25nM, EC(50) (1b)=16nM), good in vitro DMPK properties, as well as moderate oral bioavailability in monkeys (F=24%).

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • DNA-Directed RNA Polymerases / antagonists & inhibitors*
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Haplorhini
  • Pyridones / administration & dosage
  • Pyridones / chemistry
  • Pyridones / pharmacokinetics
  • Pyridones / pharmacology*
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

  • Enzyme Inhibitors
  • Pyridones
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus
  • DNA-Directed RNA Polymerases