Potent, small-molecule inhibitors of human mast cell tryptase. Antiasthmatic action of a dipeptide-based transition-state analogue containing a benzothiazole ketone

Michael J. Costanzo, Stephen C. Yabut, Harold R. Almond, Patricia Andrade-Gordon, Thomas W. Corcoran, Lawrence De Garavilla, Jack A. Kauffman, William M. Abraham, Rosario Recacha, Debashish Chattopadhyay, Bruce E. Maryanoff

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

Inhibitors of human mast cell tryptase (EC 3.4.21.59) have therapeutic potential for treating allergic or inflammatory disorders. We have investigated transition-state mimetics possessing a heterocycle-activated ketone group and identified in particular benzothiazole ketone (2S)-6 (RWJ-56423) as a potent, reversible, low-molecular-weight tryptase inhibitor with a Ki value of 10 nM. A single-crystal X-ray analysis of the sulfate salt of (2S)-6 confirmed the stereochemistry. Analogues 12 and 15-17 are also potent tryptase inhibitors. Although RWJ-56423 potently inhibits trypsin (Ki = 8.1 nM), it is selective vs other serine proteases, such as kallikrein, plasmin, and thrombin. We obtained an X-ray structure of (2S)-6 complexed with bovine trypsin (1.9-Å resolution), which depicts inter alia a hemiketal involving Ser-189, and hydrogen bonds with His-57 and Gln-192. Aerosol administration of 6 (2R,2S; RWJ-58643) to allergic sheep effectively antagonized antigen-induced asthmatic responses, with 70-75% blockade of the early response and complete ablation of the late response and airway hyperresponsiveness.

Original languageEnglish (US)
Pages (from-to)3865-3876
Number of pages12
JournalJournal of Medicinal Chemistry
Volume46
Issue number18
DOIs
StatePublished - Aug 1 2003

    Fingerprint

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Costanzo, M. J., Yabut, S. C., Almond, H. R., Andrade-Gordon, P., Corcoran, T. W., De Garavilla, L., Kauffman, J. A., Abraham, W. M., Recacha, R., Chattopadhyay, D., & Maryanoff, B. E. (2003). Potent, small-molecule inhibitors of human mast cell tryptase. Antiasthmatic action of a dipeptide-based transition-state analogue containing a benzothiazole ketone. Journal of Medicinal Chemistry, 46(18), 3865-3876. https://doi.org/10.1021/jm030050p