Discovery of novel P3-oxo inhibitor of hepatitis C virus NS3/4A serine protease

Bioorg Med Chem Lett. 2012 Apr 15;22(8):2993-6. doi: 10.1016/j.bmcl.2012.02.039. Epub 2012 Feb 22.

Abstract

A novel series of P3 oxo-modified macrocyclic hepatitis C virus NS3/4A serine protease inhibitor was designed, synthesized and biologically evaluated. The hydroxy-substituted inhibitor 10 demonstrated high potency in genotype 1a and 1b replicon and in the panel of HCV protease mutants. Interestingly, the t-butyl carbonate analog 9c, while not the most potent one in this series, exhibited a virtually flat potency profile in the panel of HCV protease mutants, thus providing opportunity for further optimization.

MeSH terms

  • Cyclopropanes
  • Drug Discovery*
  • Hepacivirus / drug effects*
  • Hepacivirus / genetics
  • Humans
  • Hydroxylation
  • Inhibitory Concentration 50
  • Isoindoles
  • Lactams / chemistry
  • Lactams / pharmacology
  • Lactams, Macrocyclic
  • Molecular Structure
  • Mutation
  • Proline / analogs & derivatives
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology
  • Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

  • Cyclopropanes
  • Isoindoles
  • Lactams
  • Lactams, Macrocyclic
  • NS3 protein, hepatitis C virus
  • Protease Inhibitors
  • Sulfonamides
  • Viral Nonstructural Proteins
  • danoprevir
  • Proline