jm6b00039_si_002.csv (2.04 kB)
Optimization of a Novel Quinazolinone-Based Series of Transient Receptor Potential A1 (TRPA1) Antagonists Demonstrating Potent in Vivo Activity
datasetposted on 2016-03-04, 14:33 authored by 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
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.