Inhibitors of hepatitis C virus NS3.4A protease. Part 3: P2 proline variants

Bioorg Med Chem Lett. 2004 Apr 19;14(8):1939-42. doi: 10.1016/j.bmcl.2004.01.078.

Abstract

We recently described the identification of an optimized alpha-ketoamide warhead for our series of HCV NS3.4A inhibitors. We report herein a series of HCV protease inhibitors incorporating 3-alkyl-substituted prolines in P(2). These compounds show exceptional enzymatic and cellular potency given their relatively small size. The marked enhancement of activity of these 3-substituted proline derivatives relative to previously reported 4-hydroxyproline derivatives constitutes additional evidence for the importance of the S(2) binding pocket as the defining pharmacophore for inhibition of the NS3.4A enzyme.

MeSH terms

  • Carrier Proteins / antagonists & inhibitors*
  • Hepatitis C / enzymology
  • Intracellular Signaling Peptides and Proteins
  • Models, Molecular
  • Molecular Structure
  • Oligopeptides / chemical synthesis
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Proline / chemical synthesis
  • Proline / chemistry
  • Proline / pharmacology*
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Proteins / antagonists & inhibitors*

Substances

  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • NS3 protein, hepatitis C virus
  • NS4A cofactor peptide, Hepatitis C virus
  • Oligopeptides
  • Viral Nonstructural Proteins
  • Viral Proteins
  • Proline