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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.*

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.

Bioorg. Chem. 98:103717 (2020)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Voltage-gated Sodium Channel ; Sodium Channel Blocker ; Disopyramide ; Drug Discovery ; Structure-activity Relationships ; Anticonvulsant Agent ; Refractory Epilepsy ; Drug Repositioning ; Medicinal Chemistry ; Cardiac Safety; Pharmacological Characterization; Antiarrhythmic-drugs; Antiepileptic Drugs; Qt Prolongation; Model; Inhibition; Discovery; Mediation; Quinidine; Epilepsy
ISSN (print) / ISBN 0045-2068
e-ISSN 1090-2120
Journal Bioorganic chemistry
Quellenangaben Volume: 98, Issue: , Pages: , Article Number: 103717 Supplement: ,
Publisher Elsevier
Publishing Place San Diego, Calif.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)