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Flupirtine and retigabine as templates for ligand-based drug design of KV7.2/3 activators

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Abstract

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 heterotetramer, voltage-gated potassium channels 2 and 3 (KV7.2/3) 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 43 compounds were synthesized and characterized with regard to KV7.2/3 opening activity and efficacy. The most active compound 22d displays excellent potency (EC50 = 4 nM) and efficacy (154%) as a KV7.2/3 opener. Limited aqueous solubility hampered toxicity testing at concentrations higher than 63 μM, but this concentration was nontoxic to two hepatocellular cell lines (HEP-G2 and TAMH) in culture. The slightly less active but more soluble compound 25b (EC50 = 11 nM, efficacy 111%) showed an improved toxicity/activity ratio compared to flupirtine by three orders of magnitude and represents an attractive lead structure for the development of safer analgesics and antiepileptics.

Graphical abstract: Flupirtine and retigabine as templates for ligand-based drug design of KV7.2/3 activators

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Publication details

The article was received on 01 Mar 2019, accepted on 05 Apr 2019 and first published on 08 Apr 2019


Article type: Paper
DOI: 10.1039/C9OB00511K
Citation: Org. Biomol. Chem., 2019, Advance Article

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    Flupirtine and retigabine as templates for ligand-based drug design of KV7.2/3 activators

    A. S. Surur, C. Bock, K. Beirow, K. Wurm, L. Schulig, M. K. Kindermann, W. Siegmund, P. J. Bednarski and A. Link, Org. Biomol. Chem., 2019, Advance Article , DOI: 10.1039/C9OB00511K

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