New K_V7.2/3 Channel Activators Exhibit Superior Toxicity and Metabolic Profiles to Flupirtine and Demonstrate...

The first-in-class K_V7.2/3 channel activator flupirtine, was considered a potent analgesic in various pain conditions. However, it was withdrawn from the market in 2018 due to severe hepatotoxicity associated with forming reactive metabolites. In this work, we present new K_V7.2/3 channel modulators that have been evaluated in several preclinical mouse pain models, including acute thermally and chemically induced pain, diabetes-induced neuropathic pain, and chemotherapy-induced peripheral neuropathy. In addition, the new K_V7.2/3 channel activators were compared with the reference substances flupirtine, retigabine, and azetukalner, focusing on the inhibition of the hERG channel, nephrotoxicity, metabolic stability, and the formation of reactive metabolites. A flupirtine analog with a pyrimidine scaffold (8) showed clear advantages over the reference compounds tested, with a favorable toxicity profile, a 2 h in vitro half-life when incubated with human liver microsomes, and a 9-fold reduction in the formation of reactive metabolites compared to flupirtine. This compound also demonstrated strong in vivo efficacy in pain models, making it a promising candidate for further development of K_V7.2/3 channel activators.