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

30 Citations (Scopus)

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

Fingerprint

Tryptases
Amides
Derivatives
Catalytic Domain
Sheep
Guinea Pigs
Animals
Asthma
Animal Models
Monomers
Crystal structure
X-Rays
Inflammation
Amino Acids
X rays
Enzymes
piperidine
Proteins

Keywords

  • Asthma
  • Inhibitor
  • Spiropiperidine
  • Tryptase

ASJC Scopus subject areas

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

Cite this

Potent, nonpeptide inhibitors of human mast cell tryptase. Synthesis and biological evaluation of novel spirocyclic piperidine amide derivatives. / Costanzo, Michael J.; Yabut, Stephen C.; Zhang, Han Cheng; White, Kimberley B.; de Garavilla, Lawrence; Wang, Yuanping; Minor, Lisa K.; Tounge, Brett A.; Barnakov, Alexander N.; Lewandowski, Frank; Milligan, Cynthia; Spurlino, John C.; Abraham, William M.; Boswell-Smith, Victoria; Page, Clive P.; Maryanoff, Bruce E.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 18, No. 6, 15.03.2008, p. 2114-2121.

Research output: Contribution to journalArticle

Costanzo, MJ, Yabut, SC, Zhang, HC, White, KB, de Garavilla, L, Wang, Y, Minor, LK, Tounge, BA, Barnakov, AN, Lewandowski, F, Milligan, C, Spurlino, JC, Abraham, WM, Boswell-Smith, V, Page, CP & Maryanoff, BE 2008, 'Potent, nonpeptide inhibitors of human mast cell tryptase. Synthesis and biological evaluation of novel spirocyclic piperidine amide derivatives', Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 6, pp. 2114-2121. https://doi.org/10.1016/j.bmcl.2008.01.093
Costanzo, Michael J. ; Yabut, Stephen C. ; Zhang, Han Cheng ; White, Kimberley B. ; de Garavilla, Lawrence ; Wang, Yuanping ; Minor, Lisa K. ; Tounge, Brett A. ; Barnakov, Alexander N. ; Lewandowski, Frank ; Milligan, Cynthia ; Spurlino, John C. ; Abraham, William M. ; Boswell-Smith, Victoria ; Page, Clive P. ; Maryanoff, Bruce E. / Potent, nonpeptide inhibitors of human mast cell tryptase. Synthesis and biological evaluation of novel spirocyclic piperidine amide derivatives. In: Bioorganic and Medicinal Chemistry Letters. 2008 ; Vol. 18, No. 6. pp. 2114-2121.
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