Identification of isoxazole-based TRPA1 inhibitors with analgesic effects in vivo

The transient receptor potential ankyrin 1 (TRPA1) channel has been extensively studied as a potential therapeutic target for the treatment of different pain types, with better efficacy and safety profiles compared to current therapies. Because TRPA1 is implicated in different pathophysiological processes, selective antagonists of this channel could provide therapeutic benefits beyond pain relief. In this study, we report the design and synthesis of a novel series of carboxamide derivatives incorporating an isoxazole moiety, which were evaluated for their ability to inhibit TRPA1-mediated signalling. Among these, we identified the TRPA1 antagonists 12 and 13 displaying nanomolar potency in vitro and significant analgesic effects against the TRPA1 agonist, allyl isothiocyanate and in the formalin test in mice. Docking analyses were also conducted to explore the binding modes of the most representative compounds with the proposed pharmacological target.