Discovery of novel TRPV3 antagonists with o-hydroxybenzoic acid as the core skeleton

As an important member of transient receptor potential (TRP) superfamily, transient receptor potential vanillin 3 (TRPV3) is a Ca²⁺ permeable, nonselective cation channel and involved in temperature perception, pain transduction, skin physiology, inflammation, cancer and other human diseases. TRPV3 agonists and antagonists are still highly demanded for the physiological function investigation of TRPV3 and drug development. In this work, a weak TRPV3 antagonist 7-1 as a hit was obtained via screening campaign of our in-house compound library. The following structure optimization work toward 7-1 afforded a novel and potent TRPV3 antagonist 7-9 whose IC₅₀ value against TRPV3 was 11.97 μM. The compound 7-9 possessed desirable selectivity to TRPV3 over other four TRP ion channels. The compound 7-9 enriches the repertoire of TRPV3 antagonist and deserves deep biological activity evaluation and further structure optimization.