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
  • 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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