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However, the K<jats:sub>v<\/jats:sub>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. Designing safer analogues lacking the structural elements leading to described side effects is an active area of current research. One of the main metabolites of flupirtine is the biologically inactive 4\u2010fluorohippuric acid. Hitherto unexplained, the proposed metabolic pathway leading to the formation of 4\u2010fluorohippuric acid from flupirtine is verified here. Through the use of eighteen flupirtine analogues, mechanistic details of this pathway could be elucidated. A possible connection with the in\u2005vitro hepatotoxicity of the flupirtine analogues and the levels of 4\u2010fluorobenzoic acid formed in enzyme incubations was examined by correlation analysis. These findings provide important information for the design of new flupirtine analogues as potential drug candidates.<\/jats:p>","DOI":"10.1002\/cmdc.202300145","type":"journal-article","created":{"date-parts":[[2023,5,12]],"date-time":"2023-05-12T05:00:45Z","timestamp":1683867645000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Structure\u2010Activity Relationships of Flupirtine Analogues for Liver Esterase\u2010Mediated Cleavage of the 4\u2010Fluorobenzylamine Moiety and Its Possible Relevance to Liver Toxicity"],"prefix":"10.1002","volume":"18","author":[{"given":"Kristin","family":"Beirow","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical\/Medicinal Chemistry Institute of Pharmacy University of Greifswald  Friedrich-Ludwig-Jahn-Str. 17 17489 Greifswald 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