Indole 5-carboxamide Thumb Pocket I inhibitors of HCV NS5B polymerase with nanomolar potency in cell-based subgenomic replicons (part 2): central amino acid linker and right-hand-side SAR studies

Bioorg Med Chem Lett. 2011 Jun 15;21(12):3664-70. doi: 10.1016/j.bmcl.2011.04.082. Epub 2011 Apr 24.

Abstract

In this part 2, new indole 5-carboxamide Thumb Pocket 1 inhibitors of HCV NS5B polymerase are described. Structure-activity relationships (SAR) were explored at the central amino acid linker position and the right-hand-side of the molecule in an attempt to identify molecules with a balanced overall profile of potency (EC(50)<100 nM), physicochemical properties and ADME characteristics.

MeSH terms

  • Allosteric Regulation
  • Amino Acid Sequence
  • Amino Acids / chemical synthesis
  • Amino Acids / chemistry*
  • Amino Acids / 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 Sequence Data
  • Molecular Structure
  • Rats
  • Solubility
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / genetics

Substances

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