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

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.