jm6b00287_si_001.pdf (211.59 kB)
Synthesis and Pharmacology of (Pyridin-2-yl)methanol Derivatives as Novel and Selective Transient Receptor Potential Vanilloid 3 Antagonists
journal contribution
posted on 2016-04-14, 00:00 authored by 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. KymTransient receptor
potential vanilloid 3 (TRPV3) is a Ca2+- 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.