2. Academic Validation
  3. 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.
PMID: 27077528 DOI: 10.1021/acs.jmedchem.6b00287
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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