52085-99-1Relevant articles and documents
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
Terrett, Jack A.,Chen, Huifen,Shore, Daniel G.,Villemure, Elisia,Larouche-Gauthier, Robin,Déry, Martin,Beaumier, Francis,Constantineau-Forget, Léa,Grand-Ma?tre, Chantal,Lépissier, Luce,Ciblat, Stéphane,Sturino, Claudio,Chen, Yong,Hu, Baihua,Lu, Aijun,Wang, Yunli,Cridland, Andrew P.,Ward, Stuart I.,Hackos, David H.,Reese, Rebecca M.,Shields, Shannon D.,Chen, Jun,Balestrini, Alessia,Riol-Blanco, Lorena,Lee, Wyne P.,Liu, John,Suto, Eric,Wu, Xiumin,Zhang, Juan,Ly, Justin Q.,La, Hank,Johnson, Kevin,Baumgardner, Matt,Chou, Kang-Jye,Rohou, Alexis,Rougé, Lionel,Safina, Brian S.,Magnuson, Steven,Volgraf, Matthew
, p. 3843 - 3869 (2021/05/04)
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 ?, revealing the binding site and mechanism of action for this class of antagonists.
