2. Academic Validation
  3. 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

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

  • J Med Chem. 2021 Apr 8;64(7):3843-3869. doi: 10.1021/acs.jmedchem.0c02023.
Jack A Terrett 1,  Huifen Chen 1,  Daniel G Shore 1,  Elisia Villemure 1,  Robin Larouche-Gauthier 2,  Martin Déry 2,  Francis Beaumier 2,  Léa Constantineau-Forget 2,  Chantal Grand-Maître 2,  Luce Lépissier 2,  Stéphane Ciblat 2,  Claudio Sturino 2,  Yong Chen 3,  Baihua Hu 3,  Aijun Lu 3,  Yunli Wang 3,  Andrew P Cridland 4,  Stuart I Ward 4,  David H Hackos 5,  Rebecca M Reese 5,  Shannon D Shields 5,  Jun Chen 6,  Alessia Balestrini 7,  Lorena Riol-Blanco 7,  Wyne P Lee 8,  John Liu 8,  Eric Suto 8,  Xiumin Wu 8,  Juan Zhang 8,  Justin Q Ly 9,  Hank La 9,  Kevin Johnson 9,  Matt Baumgardner 9,  Kang-Jye Chou 10,  Alexis Rohou 11,  Lionel Rougé 11,  Brian S Safina 1,  Steven Magnuson 1,  Matthew Volgraf 1
Affiliations

Affiliations

  • 1 Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 2 Paraza Pharma, Inc. 2525 Avenue Marie-Curie, Montreal, Quebec H4S 2E1, Canada.
  • 3 Pharmaron-Beijing Co. Ltd., 6 Taihe Road, BDA, Beijing 100176, PR China.
  • 4 Charles River Laboratories, 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
  • 5 Department of Neurosciences, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 6 Department of Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 7 Department of Discovery Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 8 Department of Translational Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 9 Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 10 Department of Small Molecule Pharmaceutical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 11 Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
PMID: 33749283 DOI: 10.1021/acs.jmedchem.0c02023
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.

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