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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