Structure-activity relationship and cardiac safety of 2-aryl-2-(pyridin-2-yl)acetamides as a new class of broad-spectrum anticonvulsants derived from Disopyramide
| Autor: | Bartłomiej Szulczyk, Jules C. Hancox, Jadwiga Turło, Eliska Mistrova, Marek Król, Jitka Sviglerova, Aziza El Harchi, Grzegorz M. Popowicz, Milan Stengl, Piotr Konopelski, Yihong Zhang, Dagmar Jarkovska, Martyna Z. Wróbel, Maciej Dawidowski, Andrzej Chodkowski, Marcin Ufnal, Piotr Szuberski, Piotr Podsadni |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
medicine.medical_treatment 01 natural sciences Biochemistry Epilepsy chemistry.chemical_compound Mice Sodium channel blocker Drug Discovery Acetamides voltage-gated sodium channel anticonvulsant agent Electroshock Molecular Structure disopyramide Anticonvulsant Agent Anticonvulsants Female Disopyramide Injections Intraperitoneal medicine.drug Stereochemistry Injections Subcutaneous sodium channel blocker drug repositioning drug discovery Structure-Activity Relationship In vivo Seizures medicinal chemistry medicine Structure–activity relationship Animals Rats Wistar Molecular Biology Dose-Response Relationship Drug 010405 organic chemistry Aryl Organic Chemistry structure-activity relationships refractory epilepsy medicine.disease 0104 chemical sciences Rats 010404 medicinal & biomolecular chemistry Anticonvulsant chemistry Pentylenetetrazole cardiac safety |
| Zdroj: | Dawidowski, M, Król, M, Szulczyk, B, Chodkowski, A, Podsadni, P, Konopelski, P, Ufnal, M, Szuberski, P, Wróbel, M Z, Zhang, Y, El Harchi, A, Hancox, J C, Jarkovska, D, Mistrova, E, Sviglerova, J, Štengl, M, Popowicz, G M & Turło, J 2020, ' Structure-activity relationship and cardiac safety of 2-aryl-2-(pyridin-2-yl)acetamides as a new class of broad-spectrum anticonvulsants derived from Disopyramide ', Bioorganic chemistry, vol. 98, 103717 . https://doi.org/10.1016/j.bioorg.2020.103717 |
| DOI: | 10.1016/j.bioorg.2020.103717 |
| Popis: | A series of 2-aryl-2-(pyridin-2-yl)acetamides were synthesized and screened for their anticonvulsant activity in animal models of epilepsy. The compounds were broadly active in the ‘classical’ maximal electroshock seizure (MES) and subcutaneous Metrazol (scMET) tests as well as in the 6 Hz and kindling models of pharmacoresistant seizures. Furthermore, the compounds showed good therapeutic indices between anticonvulsant activity and motor impairment. Structure-activity relationship (SAR) trends clearly showed the highest activity resides in unsubstituted phenyl derivatives or compounds having ortho- and meta- substituents on the phenyl ring. The 2-aryl-2-(pyridin-2-yl)acetamides were derived by redesign of the cardiotoxic sodium channel blocker Disopyramide (DISO). Our results show that the compounds preserve the capability of the parent compound to inhibit voltage gated sodium currents in patch-clamp experiments; however, in contrast to DISO, a representative compound from the series 1 displays high levels of cardiac safety in a panel of in vitro and in vivo experiments. |
| Databáze: | OpenAIRE |
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