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Letters in Drug Design & Discovery


ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Potent, Nonpeptide Inhibitors of Human Mast Cell Tryptase. 2. Investigation of the Carboxamide Portion of Spirocyclic Piperidine Amides

Author(s): Michael J. Costanzo, Stephen C. Yabut, Han-Cheng Zhang, Kimberley B. White, Yuanping Wang, Lisa K. Minor, Brett A. Tounge, Alexander N. Barnakov, Frank Lewandowski, Cynthia Milligan, John C. Spurlino and Bruce E. Maryanoff

Volume 5, Issue 2, 2008

Page: [116 - 121] Pages: 6

DOI: 10.2174/157018008783928418

Price: $65


We have explored a series of spirocyclic piperidine amide derivatives with respect to the N-acyl portion (viz. 6) for inhibition of tryptase. Thus, we identified analogues 6nn and 6oo as potent tryptase inhibitors (IC50 < 10 nM) with excellent selectivity vs. trypsin. Other interesting compounds (IC50 = 10-20 nM) in this chemical series are 6k, 6m, 6ff, and 6bbb. X-ray co-crystal structures of 6nn•tryptase and 6pp•tryptase are reported.

Keywords: Tryptase, Inhibition, Bioavailability, Asthma, Airway inflammation, Spiropiperidine

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