New K7.2/3 Channel Activators Exhibit Superior Toxicity and Metabolic Profiles to Flupirtine and Demonstrate PromisingAnalgesic Effects.

Abstract

The first-in-class K7.2/3 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 However, it was withdrawn from the market in 2018 due to severe hepatotoxicity associated with forming reactive metabolites.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 K7.2/3 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 K7.2/3 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 () showed clear advantages over the reference compounds tested, with a favorable toxicity profile, a 2 hhalf-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 strongefficacy in pain models, making it a promising candidate for further development of K7.2/3 channel activators.