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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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