Synthesis and Pharmacology of (Pyridin-2-yl)methanol Derivatives as Novel and Selective Transient Receptor Potential Vanilloid 3 Antagonists

  • J Med Chem. 2016 May 26;59(10):4926-47. doi: 10.1021/acs.jmedchem.6b00287.
Arthur Gomtsyan  1 Robert G Schmidt  1 Erol K Bayburt  1 Gregory A Gfesser  1 Eric A Voight  1 Jerome F Daanen  1 Diana L Schmidt  1 Marlon D Cowart  1 Huaqing Liu  1 Robert J Altenbach  1 Michael E Kort  1 Bruce Clapham  1 Phil B Cox  1 Anurupa Shrestha  1 Rodger Henry  1 David N Whittern  1 Regina M Reilly  1 Pamela S Puttfarcken  1 Jill-Desiree Brederson  1 Ping Song  1 Bin Li  1 Susan M Huang  1 Heath A McDonald  1 Torben R Neelands  1 Steve P McGaraughty  1 Donna M Gauvin  1 Shailen K Joshi  1 Patricia N Banfor  1 Jason A Segreti  1 Mohamad Shebley  1 Connie R Faltynek  1 Michael J Dart  1 Philip R Kym  1
Affiliations
  • 1. Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
Abstract

Transient receptor potential vanilloid 3 (TRPV3) is a CA(2+)- and Na(+)-permeable channel with a unique expression pattern. TRPV3 is found in both neuronal and non-neuronal tissues, including dorsal root ganglia, spinal cord, and keratinocytes. Recent studies suggest that TRPV3 may play a role in inflammation, pain sensation, and skin disorders. TRPV3 studies have been challenging, in part due to a lack of research tools such as selective antagonists. Herein, we provide the first detailed report on the development of potent and selective TRPV3 antagonists featuring a pyridinyl methanol moiety. Systematic optimization of pharmacological, physicochemical, and ADME properties of original lead 5a resulted in identification of a novel and selective TRPV3 antagonist 74a, which demonstrated a favorable preclinical profile in two different models of neuropathic pain as well as in a reserpine model of central pain.

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