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

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.

Cite this article as:

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