Synthesis of potent and selective 2-azepanone inhibitors of human tryptase

Bioorg Med Chem Lett. 2004 Jan 19;14(2):309-12. doi: 10.1016/j.bmcl.2003.11.016.

Abstract

The serine protease tryptase has been associated with a broad range of allergic and inflammatory diseases and, in particular, has been implicated as a critical mediator of asthma. The inhibition of tryptase therefore has the potential to be a valuable therapy for asthma. The synthesis, employing solution phase parallel methods, and SAR of a series of novel 2-azepanone tryptase inhibitors are presented. A member of this series, 8t, was identified as a potent inhibitor of human tryptase (IC(50)=38 nM) with selectivity >/=330-fold versus related serine proteases (trypsin, plasmin, uPA, tPA, APC, alpha-thrombin, and FXa) [corrected].

MeSH terms

  • Azepines / chemical synthesis*
  • Azepines / pharmacology
  • Humans
  • Serine Endopeptidases / metabolism*
  • Serine Proteinase Inhibitors / chemical synthesis*
  • Serine Proteinase Inhibitors / pharmacology
  • Tryptases

Substances

  • Azepines
  • Serine Proteinase Inhibitors
  • Serine Endopeptidases
  • Tryptases