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Profiling the activity and hepatotoxicity of flupirtine through medicinal chemistry approaches

  • Drug induced liver injury (DILI) and tissue discoloration led to the recent discontinuation of the therapeutic use of the closely related drugs flupirtine and retigabine, respectively. Experience gained with these drugs strongly suggests that heterodimer, voltage‐gated potassium channels 2 and 3 (KV2/3) are valid targets for effective treatment of pain and epilepsy. Because the adverse effects are not related to the mechanism of action, it appears promising to investigate chemical modifications of these clinically validated, drug‐like leads. In the present retro metabolic drug design study, a series of 44 compounds were synthesized and characterized with regards to KV7.2/3 opening activity and efficacy. The most active compounds displays excellent potency (EC50 = 4 nM) and efficacy (154%) as an Kv7.2/3 opener. Limited aqeous solubility hampered toxicity testing at concentrations higher than 63 μM, but this concentration was nontoxic to two hepatocellular cell ilnes (HEP‐G2 and TAMH) in culture.

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Metadaten
Author:Master of science Abdrrahman Shemsu Surur
URN:urn:nbn:de:gbv:9-opus-27418
Title Additional (German):Untersuchungen zur Aktivität und Hepatotoxizität von Flupirtin durch medizinisch-chemische Ansätze
Referee:Prof. Dr. Andreas Link, Prof. Dr. Bernhard Wünsch
Advisor:Prof. Dr. Andreas Link
Document Type:Doctoral Thesis
Language:English
Year of Completion:2019
Date of first Publication:2019/06/27
Granting Institution:Universität Greifswald, Mathematisch-Naturwissenschaftliche Fakultät
Date of final exam:2019/06/27
Release Date:2019/06/27
GND Keyword:Flupirtine, Hepatotoxicity, Kv7.2/7.3, Oxidation potential
Pagenumber:134
Faculties:Mathematisch-Naturwissenschaftliche Fakultät / Institut für Pharmazie
DDC class:500 Naturwissenschaften und Mathematik / 500 Naturwissenschaften