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

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.

• Authors: Arthur Gomtsyan, Robert G Schmidt, Erol K Bayburt, Gregory A Gfesser, Eric A Voight, Jerome F Daanen, Diana L Schmidt, Marlon D Cowart, Huaqing Liu, Robert J Altenbach, Michael E Kort, Bruce Clapham, Phil B Cox, Anurupa Shrestha, Rodger Henry, David N Whittern, Regina M Reilly, Pamela S Puttfarcken, Jill-Desiree Brederson, Ping Song, Bin Li, Susan M Huang, Heath A McDonald, Torben R Neelands, Steve P McGaraughty, Donna M Gauvin, Shailen K Joshi, Patricia N Banfor, Jason A Segreti, Mohamad Shebley, Connie R Faltynek, Michael J Dart, Philip R Kym
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 59 Issue 10 Pg. 4926-47 (05 26 2016) ISSN: 1520-4804 [Electronic] United States
• PMID: 27077528 (Publication Type: Journal Article)

Chemical References

• 3-(hydroxy(pyridin-2-yl)methyl)-1-methyl-3-(4-(trifluoromethyl)pyridin-2-yl)cyclobutanol
• Cyclobutanes
• Pyridines
• TRPV Cation Channels
• TRPV3 protein, human
• Calcium

Topics

• Calcium (metabolism)
• Cyclobutanes (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• HEK293 Cells
• Humans
• Molecular Conformation
• Pyridines (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• TRPV Cation Channels (antagonists & inhibitors, metabolism)