The synthesis and evaluation of a novel class of (E)-3-(1-cyclohexyl-1H-pyrazol-3-yl)-2-methylacrylic acid hepatitis C virus polymerase NS5B inhibitors

Bioorg Med Chem Lett. 2011 May 15;21(10):2869-72. doi: 10.1016/j.bmcl.2011.03.086. Epub 2011 Mar 30.

Abstract

Herein we report the identification and evaluation of a novel series of (E)-3-(1-cyclohexyl-1H-pyrazol-3-yl)-2-methylacrylic acid derivatives identified from a deannulation study performed on the reported benzimidazole NS5B inhibitor, 1. This resulted in the identification of (E)-3-(2-(4-((4'-cyano-4-(4-hydroxypiperidine-1-carbonyl)biphenyl-2-yl)methoxy)phenyl)-1-cyclohexyl-1H-imidazol-4-yl)-2-methylacrylic acid (11) as a potent inhibitor of NS5B. Potential pathways for the further optimization of this series are suggested.

MeSH terms

  • Hepacivirus / drug effects*
  • Humans
  • Inhibitory Concentration 50
  • Methacrylates / chemical synthesis*
  • Methacrylates / chemistry
  • Methacrylates / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Pyrazoles / chemistry*
  • Quantum Theory
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / chemistry

Substances

  • Methacrylates
  • Pyrazoles
  • Viral Nonstructural Proteins
  • methacrylic acid
  • pyrazole
  • NS-5 protein, hepatitis C virus