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.

PAR2 Mediates Itch via TRPV3 Signaling in Keratinocytes

“…These data strongly suggest that TRPV3 is involved in a PAR2-mediated scratching response. We also pretreated WT mice with intradermal injections of vehicle (8% DMSO), FSLLRY (a specific PAR2 antagonist) and 74a (a specific TRPV3 antagonist) (Gomtsyan et al, 2016;Shimada et al, 2006) to confirm the effects of PAR2 and TRPV3 on scratching behavior. As expected, the number of scratches induced by SLIGRL, trypsin, and 2fly decreased significantly when TRPV3 and PAR2 were pharmacologically blocked ( Figure 1b).…”

Targeting nociceptive transient receptor potential channels to treat chronic pain: current state of the field

“…Several companies have pursued selective antagonists of TRPV3 channels including Abbvie (Gomtsyan et al, ), Hydra Biosciences and Glenmark/Sanofi‐Aventis (Grubisha et al, ). The Glenmark/Sanofi‐Aventis compound GRC15300 failed a Phase 2 trial in chronic peripheral neuropathy patients (a 4 week trial), and the collaboration between the two companies was terminated in 2014 (Broad et al, ).…”

TRPV3 in Drug Development

“…The same group has also reported that 17(R)-resolvin D, an endogenous TRPV3 antagonist, is anti-nociceptive in acute and inflammatory pain states [ 24 ]. Complementarily, tool antagonist molecules from Hydra, Glenmark and AbbVie described below have attenuated pain behaviors in a number of pre-clinical pain models, including primarily carrageenan and Complete Freund’s Adjuvant-induced thermal and/or tactile hypersensitivity, but also in nerve ligation models [ 63 , 67 , 68 ].…”

“…In recent years, AbbVie have been active in the TRPV3 arena, publishing several patents [ 85 , 86 ] and more recently a paper [ 67 ]. They describe a series of compounds, some displaying mid-nanomolar potency in blocking 2-APB-stimulated calcium influx in assays using recombinant human and mouse TRPV3 channels.…”