TY - THES U1 - Dissertation / Habilitation A1 - Surur, Abdrrahman Shemsu T1 - Profiling the activity and hepatotoxicity of flupirtine through medicinal chemistry approaches N2 - 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. KW - Flupirtine KW - Kv7.2/7.3 KW - Hepatotoxicity KW - Oxidation potential Y2 - 2019 U6 - https://nbn-resolving.org/urn:nbn:de:gbv:9-opus-27418 UN - https://nbn-resolving.org/urn:nbn:de:gbv:9-opus-27418 SP - 134 S1 - 134 ER -