Potent, nonpeptide inhibitors of human mast cell tryptase. Synthesis and biological evaluation of novel spirocyclic piperidine amide derivatives

  • Bioorg Med Chem Lett. 2008 Mar 15;18(6):2114-21. doi: 10.1016/j.bmcl.2008.01.093.
Michael J Costanzo  1 ,  Stephen C Yabut ,  Han-Cheng Zhang ,  Kimberley B White ,  Lawrence de Garavilla ,  Yuanping Wang ,  Lisa K Minor ,  Brett A Tounge ,  Alexander N Barnakov ,  Frank Lewandowski ,  Cynthia Milligan ,  John C Spurlino ,  William M Abraham ,  Victoria Boswell-Smith ,  Clive P Page ,  Bruce E Maryanoff
Affiliations
  • 1. Research and Early Development, Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, PA 19477-0776, USA. [email protected]
PMID: 18272363 DOI: 10.1016/j.bmcl.2008.01.093
Abstract

We have explored a series of spirocyclic piperidine amide derivatives (5) as tryptase inhibitors. Thus, 4 (JNJ-27390467) was identified as a potent, selective tryptase inhibitor with oral efficacy in two animal models of airway inflammation (sheep and guinea pig Asthma models). An X-ray co-crystal structure of 4 x tryptase revealed a hydrophobic pocket in the enzyme's active site, which is induced by the phenylethynyl group and is comprised of amino acid residues from two different monomers of the tetrameric protein.

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