Abstract
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
Letters in Drug Design & Discovery
Title: Potent, Nonpeptide Inhibitors of Human Mast Cell Tryptase. 2. Investigation of the Carboxamide Portion of Spirocyclic Piperidine Amides
Volume: 5 Issue: 2
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
Affiliation:
Keywords: Tryptase, Inhibition, Bioavailability, Asthma, Airway inflammation, Spiropiperidine
Abstract: 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.
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Costanzo J. Michael, Yabut C. Stephen, Zhang Han-Cheng, White B. Kimberley, Wang Yuanping, Minor K. Lisa, Tounge A. Brett, Barnakov N. Alexander, Lewandowski Frank, Milligan Cynthia, Spurlino C. John and Maryanoff E. Bruce, Potent, Nonpeptide Inhibitors of Human Mast Cell Tryptase. 2. Investigation of the Carboxamide Portion of Spirocyclic Piperidine Amides, Letters in Drug Design & Discovery 2008; 5 (2) . https://dx.doi.org/10.2174/157018008783928418
DOI https://dx.doi.org/10.2174/157018008783928418 |
Print ISSN 1570-1808 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-628X |
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