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Synthesis and potassium KV7 channel opening activity of thioether analogues of the analgesic flupirtine

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Abstract

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.

Graphical abstract: Synthesis and potassium KV7 channel opening activity of thioether analogues of the analgesic flupirtine

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Publication details

The article was received on 12 Oct 2018, accepted on 29 Oct 2018 and first published on 30 Oct 2018


Article type: Communication
DOI: 10.1039/C8OB02530D
Citation: Org. Biomol. Chem., 2018, Advance Article
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    Synthesis and potassium KV7 channel opening activity of thioether analogues of the analgesic flupirtine

    C. Bock, K. Beirow, A. S. Surur, L. Schulig, A. Bodtke, P. J. Bednarski and A. Link, Org. Biomol. Chem., 2018, Advance Article , DOI: 10.1039/C8OB02530D

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