Flupirtine and retigabine as templates for ligand-based drug design of KV7.2/3 activators. Issue 18 (16th April 2019)

• Record Type: Journal Article
• Authors: Surur, Abdrrahman S.; Bock, Christian; Beirow, Kristin; Wurm, Konrad; Schulig, Lukas; Kindermann, Markus K.; Siegmund, Werner; Bednarski, Patrick J.; Link, Andreas
• Is Part Of: Organic & biomolecular chemistry. Volume 17:Issue 18(2019)
• Page Start: 4512
• Page End: 4522
• Publication Date: 2019-04-16
• Subjects: Chemistry, Organic -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1039/c9ob00511k
• Languages: English
• ISSNs: 1477-0520

Abstract

Abstract : Puzzling stability: molecular jigsaw pieces of residues characterized in light of activity, lipophilicity, stability against oxidation, and hepatotoxicity were combined to yield flupirtine analogue25b . 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 (KV 7.2/3) 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 KV 7.2/3 opening activity and efficacy. The most active compound22d displays excellent potency (EC50 = 4 nM) and efficacy (154%) as a KV 7.2/3 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 compound25b (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.