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Structure-Activity Relationships of Flupirtine Analogues for Liver Esterase-Mediated Cleavage of the 4-Fluorobenzylamine Moiety and Its Possible Relevance to Liver Toxicity
- Flupirtine and retigabine were essential drugs to combat pain and epilepsy. However, the Kv7 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-fluorohippuric acid. Hitherto unexplained, the proposed metabolic pathway leading to the formation of 4-fluorohippuric 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 vitro hepatotoxicity of the flupirtine analogues and the levels of 4-fluorobenzoic 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.
Author: | Kristin Beirow, Julia Jedamzik, Lukas Schulig, Konrad W. Wurm, Christian J. Lemmerhirt, Robert K. Hofstetter, Andreas Link, Patrick J. BednarskiORCiD |
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URN: | urn:nbn:de:gbv:9-opus-108013 |
DOI: | https://doi.org/10.1002/cmdc.202300145 |
ISSN: | 1860-7187 |
Parent Title (English): | ChemMedChem |
Publisher: | Wiley |
Place of publication: | Hoboken, NJ |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2023/05/12 |
Date of first Publication: | 2023/07/17 |
Release Date: | 2024/03/04 |
Tag: | carboxyesterase; flupirtine; metabolism; retigabine; structure-activity relationships |
Volume: | 18 |
Issue: | 14 |
Article Number: | e202300145 |
Page Number: | 9 |
Faculties: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Pharmazie |
Collections: | weitere DFG-förderfähige Artikel |
Licence (German): | Creative Commons - Namensnennung-Nicht kommerziell-Keine Bearbeitung 4.0 International |