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

Michael J. Costanzo, 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

Research output: Contribution to journalArticle

33 Scopus citations

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 · 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.

Original languageEnglish (US)
Pages (from-to)2114-2121
Number of pages8
JournalBioorganic and Medicinal Chemistry Letters
Volume18
Issue number6
DOIs
StatePublished - Mar 15 2008

Keywords

  • Asthma
  • Inhibitor
  • Spiropiperidine
  • Tryptase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Fingerprint Dive into the research topics of 'Potent, nonpeptide inhibitors of human mast cell tryptase. Synthesis and biological evaluation of novel spirocyclic piperidine amide derivatives'. Together they form a unique fingerprint.

  • Cite this

    Costanzo, M. J., Yabut, S. C., Zhang, H. C., White, K. B., de Garavilla, L., Wang, Y., Minor, L. K., Tounge, B. A., Barnakov, A. N., Lewandowski, F., Milligan, C., Spurlino, J. C., Abraham, W. M., Boswell-Smith, V., Page, C. P., & Maryanoff, B. E. (2008). Potent, nonpeptide inhibitors of human mast cell tryptase. Synthesis and biological evaluation of novel spirocyclic piperidine amide derivatives. Bioorganic and Medicinal Chemistry Letters, 18(6), 2114-2121. https://doi.org/10.1016/j.bmcl.2008.01.093