Discovery of an irreversible HCV NS5B polymerase inhibitor

Bioorg Med Chem Lett. 2013 Dec 15;23(24):6585-7. doi: 10.1016/j.bmcl.2013.10.060. Epub 2013 Nov 6.

Abstract

The discovery of lead compound 2e was described. Its covalent binding to HCV NS5B polymerase enzyme was investigated by X-ray analysis. The results of distribution, metabolism and pharmacokinetics were reported. Compound 2e was demonstrated to be potent (replicon GT-1b EC50 = 0.003 μM), highly selective, and safe in in vitro and in vivo assays.

Keywords: HCV; NS5B polymerase.

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Dogs
  • Drug Evaluation, Preclinical
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Haplorhini
  • Hepacivirus / enzymology*
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry*
  • Indoles / pharmacokinetics
  • Indoles / pharmacology
  • Male
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Structure, Tertiary
  • Quinolines / chemical synthesis
  • Quinolines / chemistry*
  • Quinolines / pharmacokinetics
  • Quinolines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / metabolism

Substances

  • Enzyme Inhibitors
  • Indoles
  • Quinolines
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus