Structure-Activity Relationships of Flupirtine Analogues for Liver Esterase-Mediated Cleavage of the 4-Fluorobenzylamine Moiety and Its Possible Relevance to Liver Toxicity

Flupirtine and retigabine were essential drugs to combat pain and epilepsy. However, the K(v)7 potassium channel openers are fraught with hepatotoxicity and tissue discoloration, respectively, limiting their therapeutic value. Both adverse events are likely due to reactive metabolites arising from oxidative metabolism. Designing safer analogues lacking the structural elements leading to described side effects is an active area of current research. One of the main metabolites of flupirtine is the biologically inactive 4-fluorohippuric acid. Hitherto unexplained, the proposed metabolic pathway leading to the formation of 4-fluorohippuric acid from flupirtine is verified here. Through the use of eighteen flupirtine analogues, mechanistic details of this pathway could be elucidated. A possible connection with the in vitro hepatotoxicity of the flupirtine analogues and the levels of 4-fluorobenzoic acid formed in enzyme incubations was examined by correlation analysis. These findings provide important information for the design of new flupirtine analogues as potential drug candidates.

Automated summary

Flupirtine and retigabine are important drugs for pain and epilepsy, but they have limitations due to hepatotoxicity and tissue discoloration. They are metabolized to reactive metabolites, which cause adverse effects. The metabolic pathway leading to the formation of biologically inactive 4-fluorohippuric acid from flupirtine has been verified through the use of flupirtine analogues. The correlation between in vitro hepatotoxicity and the levels of 4-fluorobenzoic acid may provide valuable information for the design of new flupirtine analogues.