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
| Autor: | Jun Chen, Baihua Hu, Kevin M. Johnson, Kang-Jye Chou, Jack A. Terrett, Yunli Wang, Lea Constantineau-Forget, Steven Magnuson, Chantal Grand-Maître, Francis Beaumier, John Liu, Lorena Riol-Blanco, Shannon D. Shields, Yong Chen, Brian Safina, Martin Dery, Elisia Villemure, Claudio Sturino, Huifen Chen, Luce Lépissier, Matthew Volgraf, Alessia Balestrini, Xiumin Wu, Daniel G. Shore, Stuart Ward, Wyne P. Lee, David H. Hackos, Andrew Peter Cridland, Robin Larouche-Gauthier, Lionel Rouge, Stephane Ciblat, Aijun Lu, Matt Baumgardner, Justin Ly, Rebecca M. Reese, Alexis Rohou, Eric Suto, Juan Zhang, Hank La |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Ovalbumin Guinea Pigs CHO Cells Ligands 01 natural sciences Rats Sprague-Dawley Structure-Activity Relationship 03 medical and health sciences Transient receptor potential channel Cricetulus Drug Discovery medicine Animals Humans Structure–activity relationship Ankyrin Binding site Furans TRPA1 Cation Channel Ion channel 030304 developmental biology Inflammation chemistry.chemical_classification Oxadiazoles 0303 health sciences Molecular Structure biology Chemistry biology.organism_classification Small molecule Asthma 0104 chemical sciences 010404 medicinal & biomolecular chemistry Mechanism of action Purines Biophysics Molecular Medicine medicine.symptom Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry. 64:3843-3869 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.0c02023 |
| Popis: | 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 A, revealing the binding site and mechanism of action for this class of antagonists. |
| Databáze: | OpenAIRE |
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