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
Jack A. Terrett, Huifen Chen, Daniel G. Shore, Elisia Villemure, Robin Larouche‐Gauthier, Martin Déry, Francis Beaumier, Léa Constantineau-Forget, Chantal Grand‐Maître, Luce Lépissier, Stéphane Ciblat, Claudio F. Sturino, Yong Chen, Baihua Hu, Aijun Lu, Yunli Wang, Andrew P. Cridland, Stuart I. Ward, David H. Hackos, Rebecca M. Reese, Shannon D. Shields, Jun Chen, Alessia Balestrini, Lorena Riol‐Blanco, Wyne P. Lee, John Liu, Eric Suto, Xiumin Wu, Juan Zhang, Justin Q. Ly, Hank La, Kevin M. Johnson, Matt Baumgardner, Kang-Jye Chou, Alexis Rohou, Lionel Rougé, Brian S. Safina, Steven Magnuson, Matthew Volgraf
Abstract
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.