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

Transient 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.