| Literature DB >> 26942860 |
Laurie B Schenkel1,2, Philip R Olivieri1,2, Alessandro A Boezio1,2, Holly L Deak1,2, Renee Emkey1,2, Russell F Graceffa1,2, Hakan Gunaydin1,2, Angel Guzman-Perez1,2, Josie H Lee1,2, Yohannes Teffera1,2, Weiya Wang1,2, Beth D Youngblood1,2, Violeta L Yu1,2, Maosheng Zhang1,2, Narender R Gavva1,2, Sonya G Lehto1,2, Stephanie Geuns-Meyer1,2.
Abstract
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 intrinsic 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.Entities:
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Year: 2016 PMID： 26942860 DOI： 10.1021/acs.jmedchem.6b00039
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446