6-(Azaindol-2-yl)pyridine-3-sulfonamides as potent and selective inhibitors targeting hepatitis C virus NS4B

Bioorg Med Chem Lett. 2015 Feb 15;25(4):781-6. doi: 10.1016/j.bmcl.2014.12.093. Epub 2015 Jan 7.

Abstract

A structure-activity relationship investigation of various 6-(azaindol-2-yl)pyridine-3-sulfonamides using the HCV replicon cell culture assay led to the identification of a potent series of 7-azaindoles that target the hepatitis C virus NS4B. Compound 2ac, identified via further optimization of the series, has excellent potency against the HCV 1b replicon with an EC50 of 2nM and a selectivity index of >5000 with respect to cellular GAPDH RNA. Compound 2ac also has excellent oral plasma exposure levels in rats, dogs and monkeys and has a favorable liver to plasma distribution profile in rats.

Keywords: 6-(Azaindol-2-yl)pyridine-3-sulfonamides; HCV inhibitors; NS4B; Replicon; Structure–activity relationship.

MeSH terms

  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Dogs
  • Hepacivirus / drug effects
  • Hepacivirus / enzymology*
  • Humans
  • Macaca fascicularis
  • Pyridines / chemistry*
  • Pyridines / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Sulfonamides / pharmacology*
  • Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

  • Antiviral Agents
  • NS4B protein, flavivirus
  • Pyridines
  • Sulfonamides
  • Viral Nonstructural Proteins