P1 and P3 optimization of novel bicycloproline P2 bearing tetrapeptidyl alpha-ketoamide based HCV protease inhibitors

Bioorg Med Chem Lett. 2004 Jan 5;14(1):257-61. doi: 10.1016/j.bmcl.2003.09.075.

Abstract

With the aim of discovering potent and selective HCV protease inhibitors, we synthesized and evaluated a series of 1a based tetrapeptidyl ketoamides with additional modification(s) at P1', P1, and P3 positions. As a result of this effort, we found that replacement of the P3 valine with tert-leucine resulted in the discovery of a series of inhibitors (e.g., 3a, 3c, and 4c) endowed with improved enzyme and/or cellular activity relative to 1a. When dosed to F-344 rats orally at 50mg/kg, 3a achieved 2.5x higher liver and plasma exposure in comparison to that detected with 1a.

MeSH terms

  • Animals
  • Bridged Bicyclo Compounds / chemistry
  • Cell Line, Tumor
  • Hepacivirus / drug effects*
  • Hepacivirus / enzymology*
  • Humans
  • Liver / drug effects
  • Liver / enzymology
  • Liver / virology
  • Male
  • Proline / chemistry*
  • Proline / pharmacology
  • Rats
  • Rats, Inbred F344
  • Rats, Sprague-Dawley
  • Serine Endopeptidases / metabolism*
  • Serine Proteinase Inhibitors / chemical synthesis*
  • Serine Proteinase Inhibitors / pharmacology
  • Viral Nonstructural Proteins / metabolism*

Substances

  • Bridged Bicyclo Compounds
  • NS3 protein, hepatitis C virus
  • Serine Proteinase Inhibitors
  • Viral Nonstructural Proteins
  • Proline
  • Serine Endopeptidases