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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

2021; American Chemical Society; Volume: 64; Issue: 7 Linguagem: Inglês

10.1021/acs.jmedchem.0c02023

1520-4804

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,

Phytochemicals and Antioxidant Activities

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