Sulfide Analogues of Flupirtine and Retigabine with Nanomolar KV7.2/KV7.3 Channel Opening Activity

• Published in: ChemMedChem Vol. 14; no. 9; pp. 952 - 964
• Main Authors: Bock, Christian, Surur, Abdrrahman S., Beirow, Kristin, Kindermann, Markus K., Schulig, Lukas, Bodtke, Anja, Bednarski, Patrick J., Link, Andreas
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 06.05.2019; Wiley Subscription Services, Inc
• Subjects: Analgesics; Aromatic compounds; Channel opening; Chemistry, Medicinal; Discoloration; flupirtine; Hepatotoxicity; KCNQ; KV7; Life Sciences & Biomedicine; Metabolites; Oxidation; Pharmacology & Pharmacy; Potassium; Potassium channels (voltage-gated); Quinones; retigabine; Science & Technology; Sulfide; Sulfides; Tissues; Toxicity; DISCOLORATION; SULFOXIMINES; POTENT; K(V)7; retigabine; flupirtine; KCNQ; SKIN; RECEPTORS; DERIVATIVES; DISCOVERY; sulfides
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201900112

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. The road to hell is paved with oxidation. Flupirtine may be innocuous by itself, but suffers from oxidative biotransformation into toxic metabolites, leaving its validated target (KV7 channels) vastly underexploited. Herein we present a library of sulfide analogues of flupirtine that change the track from toxic quinone imine metabolism in favor of benign sulfoxide formation. The rationale of this approach is supported by structure–activity relationship studies.