Puzzling stability: molecular jigsaw pieces of residues characterized in light of activity, lipophilicity, stability against oxidation, and hepatotoxicity were combined to yield flupirtine analogue 25b.

The potassium channel openers flupirtine and retigabine have proven to be valuable analgesics or antiepileptics. Their recent withdrawal due to occasional hepatotoxicity and tissue discoloration, respectively, leaves a therapeutic niche unfilled. Metabolic oxidation of both drugs gives rise to the formation of electrophilic quinones. These elusive, highly reactive metabolites may induce liver injury in the case of flupirtine and blue tissue discoloration after prolonged intake of retigabine. We examined which structural features can be altered to avoid the detrimental oxidation of the aromatic ring and shift oxidation toward the formation of more benign metabolites. Structure–activity relationship studies were performed to evaluate the KV7.2/3 channel opening activity of 45 derivatives. Sulfide analogues were identified that are devoid of the risk of quinone formation, but possess potent KV7.2/3 opening activity. For example, flupirtine analogue 3‐(3,5‐difluorophenyl)‐N‐(6‐(isobutylthio)‐2‐(pyrrolidin‐1‐yl)pyridin‐3‐yl)propanamide (48) has 100‐fold enhanced activity (EC50=1.4 nm), a vastly improved toxicity/activity ratio, and the same efficacy as retigabine in vitro.

Neuronal voltage‐gated potassium channels KV7.2/KV7.3 are sensitive to small‐molecule drugs such as flupirtine, even though physiological response occurs in the absence of ligands. Clinically, prolonged use of flupirtine as a pain medication is associated with rare cases of drug‐induced liver injury. Thus, safety concerns prevent a broader use of this non‐opioid and non‐steroidal analgesic in therapeutic areas with unmet medical needs such as hyperactive bladder or neonatal seizures. With the goal of studying influences of chemical structure on activity and toxicity of flupirtine, we explored modifications of the benzylamino bridge and the substitution pattern in both rings of flupirtine. Among twelve derivatives, four novel thioether derivatives showed the desired activity in cellular assays and may serve as leads for safer KV channel openers.

Benign by design: active sulfide-analogues of potassium channel opener flupirtine do not form reactive oxidation products in vitro.