Flupirtine and retigabine as templates for ligand-based drug design of KV7.2/3 activators
| العنوان: | Flupirtine and retigabine as templates for ligand-based drug design of KV7.2/3 activators |
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| المؤلفون: | Andreas Link, Abdrrahman Shemsu Surur, Kristin Beirow, Werner Siegmund, Lukas Schulig, Christian Bock, Konrad Wurm, Markus K. Kindermann, Patrick J. Bednarski |
| المصدر: | Organic & Biomolecular Chemistry. 17:4512-4522 |
| بيانات النشر: | Royal Society of Chemistry (RSC), 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Drug, 0303 health sciences, media_common.quotation_subject, Retigabine, Organic Chemistry, Pharmacology, Biochemistry, Orders of magnitude (mass), 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Mechanism of action, chemistry, Toxicity, medicine, Potency, Physical and Theoretical Chemistry, medicine.symptom, Flupirtine, 030217 neurology & neurosurgery, 030304 developmental biology, medicine.drug, media_common, EC50 |
| الوصف: | 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. |
| تدمد: | 1477-0539 1477-0520 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::e1a280d5b35dba6960e3f225f79ce425 https://doi.org/10.1039/c9ob00511k |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi...........e1a280d5b35dba6960e3f225f79ce425 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14770539 14770520 |
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