Tetrahydrofuran-Based Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonists: Ligand-Based Discovery, Activity in a Rodent Asthma Model, and Mechanism-of-Action via Cryogenic Electron Microscopy

Transient
receptor potential ankyrin 1 (TRPA1) is a nonselective
calcium-permeable ion channel highly expressed in the primary sensory
neurons functioning as a polymodal sensor for exogenous and endogenous
stimuli and has generated widespread interest as a target for inhibition
due to its implication in neuropathic pain and respiratory disease.
Herein, we describe the optimization of a series of potent, selective,
and orally bioavailable TRPA1 small molecule antagonists, leading
to the discovery of a novel tetrahydrofuran-based linker. Given the
balance of physicochemical properties and strong in vivo target engagement in a rat AITC-induced pain assay, compound 20 was progressed into a guinea pig ovalbumin asthma model
where it exhibited significant dose-dependent reduction of inflammatory
response. Furthermore, the structure of the TRPA1 channel bound to
compound 21 was determined via cryogenic electron microscopy
to a resolution of 3 Å, revealing the binding site and mechanism
of action for this class of antagonists.