Potent bisimidazole-based HCV NS5A inhibitors bearing annulated tricyclic motifs

Bioorg Med Chem Lett. 2014 Dec 15;24(24):5738-5742. doi: 10.1016/j.bmcl.2014.10.056. Epub 2014 Oct 22.

Abstract

This Letter describes the synthesis and biological evaluation of a number of functionalized bisimidazoles bearing annulated tricyclic motifs as potent inhibitors of HCV NS5A protein. Compound 4 h, which contains a substituted tricyclic 6-6-6 xanthene, demonstrated broad genotypic spectrum, compelling potency, and good oral bioavailability with dose-dependent drug exposure level in multiple animal species.

Keywords: Annulated tricyclic; Bisimidazole; HCV; NS5A inhibitor.

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacokinetics
  • Cyclization
  • Dogs
  • Genotype
  • Half-Life
  • Haplorhini
  • Hepacivirus / genetics
  • Hepacivirus / metabolism*
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry*
  • Imidazoles / pharmacokinetics
  • Rats
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / metabolism
  • Xanthenes / chemical synthesis
  • Xanthenes / chemistry*
  • Xanthenes / pharmacokinetics

Substances

  • Antiviral Agents
  • Imidazoles
  • Viral Nonstructural Proteins
  • Xanthenes
  • imidazole
  • NS-5 protein, hepatitis C virus