Discovery of GS-9669, a thumb site II non-nucleoside inhibitor of NS5B for the treatment of genotype 1 chronic hepatitis C infection

J Med Chem. 2014 Mar 13;57(5):1893-901. doi: 10.1021/jm401420j. Epub 2013 Nov 6.

Abstract

Investigation of thiophene-2-carboxylic acid HCV NS5B site II inhibitors, guided by measurement of cell culture medium binding, revealed the structure-activity relationships for intrinsic cellular potency. The pharmacokinetic profile was enhanced through incorporation of heterocyclic ethers on the N-alkyl substituent. Hydroxyl groups were incorporated to modulate protein binding. Intrinsic potency was further improved through enantiospecific introduction of an olefin in the N-acyl motif, resulting in the discovery of the phase 2 clinical candidate GS-9669. The unexpected activity of this compound against the clinically relevant NS5B M423T mutant, relative to the wild type, was shown to arise from both the N-alkyl substituent and the N-acyl group.

MeSH terms

  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Furans / chemistry
  • Furans / pharmacology*
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*
  • Viral Nonstructural Proteins / chemistry
  • Viral Nonstructural Proteins / pharmacology*

Substances

  • Antiviral Agents
  • Enzyme Inhibitors
  • Furans
  • GS-9669
  • Thiophenes
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus

Associated data

  • PDB/4EO6