Optimization of a Novel Quinazolinone-Based Series of Transient Receptor Potential A1 (TRPA1) Antagonists Demonstrating Potent in Vivo Activity

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• 作者：Laurie B. Schenkel ; Philip R. Olivieri ; Alessandro A. Boezio ; Holly L. Deak ; Renee Emkey ; Russell F. Graceffa ; Hakan Gunaydin ; Angel Guzman-Perez ; Josie H. Lee ; Yohannes Teffera ; Weiya Wang ; Beth D. Youngblood ; Violeta L. Yu ; Maosheng Zhang ; Narender R. Gavva ; Sonya G. Lehto ; Stephanie Geuns-Meyer
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：March 24, 2016
• 年：2016
• 卷：59
• 期：6
• 页码：2794-2809
• 全文大小：629K
• ISSN：1520-4804

文摘

There has been significant interest in developing a transient receptor potential A1 (TRPA1) antagonist for the treatment of pain due to a wealth of data implicating its role in pain pathways. Despite this, identification of a potent small molecule tool possessing pharmacokinetic properties allowing for robust in vivo target coverage has been challenging. Here we describe the optimization of a potent, selective series of quinazolinone-based TRPA1 antagonists. High-throughput screening identified 4, which possessed promising potency and selectivity. A strategy focused on optimizing potency while increasing polarity in order to improve intrinisic clearance culminated with the discovery of purinone 27 (AM-0902), which is a potent, selective antagonist of TRPA1 with pharmacokinetic properties allowing for >30-fold coverage of the rat TRPA1 IC₅₀ in vivo. Compound 27 demonstrated dose-dependent inhibition of AITC-induced flinching in rats, validating its utility as a tool for interrogating the role of TRPA1 in in vivo pain models.