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

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

Affiliation

  • 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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