From benzimidazole to indole-5-carboxamide Thumb Pocket I inhibitors of HCV NS5B polymerase. Part 1: indole C-2 SAR and discovery of diamide derivatives with nanomolar potency in cell-based subgenomic replicons

Bioorg Med Chem Lett. 2011 Jun 15;21(12):3658-63. doi: 10.1016/j.bmcl.2011.04.059. Epub 2011 Apr 20.

Abstract

Replacement of the benzimidazole core of allosteric Thumb Pocket 1 HCV NS5B finger loop inhibitors by more lipophilic indole derivatives provided up to 30-fold potency improvements in cell-based subgenomic replicon assays. Optimization of C-2 substitution on the indole core led to the identification of analogs with EC(50)<100 nM and modulated the pharmacokinetic properties of the inhibitors based on preliminary data from in vitro ADME profiles and in vivo rat PK.

MeSH terms

  • Allosteric Regulation
  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / pharmacology
  • Animals
  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology
  • Caco-2 Cells
  • Hepacivirus / drug effects*
  • Hepacivirus / enzymology
  • Hepacivirus / genetics
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Inhibitory Concentration 50
  • Molecular Structure
  • Rats
  • Solubility
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / genetics

Substances

  • Amides
  • Benzimidazoles
  • Indoles
  • Viral Nonstructural Proteins
  • indole-5-carboxamide
  • NS-5 protein, hepatitis C virus