Benzimidazole-containing HCV NS5A inhibitors: effect of 4-substituted pyrrolidines in balancing genotype 1a and 1b potency

Bioorg Med Chem Lett. 2015 Feb 15;25(4):944-7. doi: 10.1016/j.bmcl.2014.12.045. Epub 2014 Dec 20.

Abstract

The treatment of HCV with highly efficacious, well-tolerated, interferon-free regimens is a compelling clinical goal. Trials employing combinations of direct-acting antivirals that include NS5A inhibitors have shown significant promise in meeting this challenge. Herein, we describe our efforts to identify inhibitors of NS5A and report on the discovery of benzimidazole-containing analogs with subnanomolar potency against genotype 1a and 1b replicons. Our SAR exploration of 4-substituted pyrrolidines revealed that the subtle inclusion of a 4-methyl group could profoundly increase genotype 1a potency in multiple scaffold classes.

Keywords: HCV; Hepatitis C virus; NS5A.

MeSH terms

  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Genotype
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology*
  • Viral Nonstructural Proteins / drug effects*

Substances

  • Antiviral Agents
  • Benzimidazoles
  • Pyrrolidines
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus