Research Information System University of Greifswald

Bock C*¹, Beirow K², S. Surur A¹, Schulig L¹, Bodtke A¹, J. Bednarski P², Link A¹

1 - Institut für Pharmazie / AG Pharmazeutische/Medizinische Chemie

2 - Institut für Pharmazie / AG Pharmazeutische und Medizinische Chemie

Flupirtine, an opener of neuronal voltage gated potassium channels (KV7.2/3), has been used as a therapeutic alternative for pain treatment in patients refractory to NSAIDs and opioids. Because flupirtine is associated with rare but fatal drug-induced liver injury that may result from the formation of toxic metabolites upon metabolic oxidation, we synthesized novel derivatives with the goal of identifying equally active and ultimately safer KV7.2/3 channel openers. Four thioether analogues were designed to lack a nitrogen atom that would be a prerequisite for the formation of toxic para-quinone diimines, and form sulfoxide and sulfone metabolites instead. KV7.2/3 channel opening activity and hepatotoxicity data of twelve novel flupirtine analogues, four thioethers and their respective sulfoxide and sulfone metabolites are reported.