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 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.

Oxidation potentials of N-modified derivatives of the analgesic flupirtine linked to potassium KV 7 channel opening activity but not hepatocyte toxicity.

Openers of neuronal voltage-gated potassium channels (KV ) are of interest as therapeutic agents for treating pain (flupirtine) and epilepsy (retigabine). In an effort to better understand the mechanisms of action and toxicity of flupirtine, we synthesized nine novel analogues with varying redox behavior. Flupirtine can be oxidatively metabolized into azaquinone diimines; thus, the oxidation potentials of flupirtine and its analogues were measured by cyclic voltammetry.