Highly potent non-peptidic inhibitors of the HCV NS3/NS4A serine protease

Bioorg Med Chem Lett. 2002 Nov 4;12(21):3129-33. doi: 10.1016/s0960-894x(02)00680-7.

Abstract

Screening of a diverse set of bisbenzimidazoles for inhibition of the hepatitis C virus (HCV) serine protease NS3/NS4A led to the identification of a potent Zn(2+)-dependent inhibitor (1). Optimization of this screening hit afforded a 10-fold more potent inhibitor (46) under Zn(2+) conditions (K(i)=27nM). This compound (46) binds also to NS3/NS4A in a Zn(2+) independent fashion (K(i)=1microM). The SAR of this class of compounds under Zn(2+) conditions is highly divergent compared to the SAR in the absence of Zn(2+), suggesting two distinct binding modes.

MeSH terms

  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / pharmacology*
  • Edetic Acid
  • Hepacivirus / enzymology*
  • Indicators and Reagents
  • Peptides / chemical synthesis
  • Peptides / pharmacology
  • RNA, Viral / chemistry
  • RNA, Viral / genetics
  • Serine Proteinase Inhibitors / chemical synthesis*
  • Serine Proteinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Zinc / pharmacology

Substances

  • Benzimidazoles
  • Indicators and Reagents
  • NS3 protein, hepatitis C virus
  • NS4 protein, hepatitis C virus
  • Peptides
  • RNA, Viral
  • Serine Proteinase Inhibitors
  • Viral Nonstructural Proteins
  • Edetic Acid
  • Zinc