N-Benzyl-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) with Hybrid Structure as a Candidate for a Broad-Spectrum Antiepileptic Drug

• DOI: 10.1007/s13311-019-00773-w
• Publication Date: 2019-09-04T17:02:58Z
• Authors: Krzysztof Kamiński; Katarzyna Socała; Mirosław Zagaja; Marta Andres-Mach; Michał Abram; Marcin Jakubiec; Mateusz Pieróg; Dorota Nieoczym; Anna Rapacz; Kinga Gawel; Camila V. Esguerra; Gniewomir Latacz; Annamaria Lubelska; Bartłomiej Szulczyk; Aleksandra Szewczyk; Jarogniew Jacek Ł...; Piotr Wlaź
• Keywords: Kindling model; Valproic Acid; Broad spectrum; ED50

In our recent studies, we identified compound N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) as a broad-spectrum hybrid anticonvulsant which showed potent protection across the most important animal acute seizure models such maximal electroshock (MES) test, subcutaneous pentylenetetrazole (s.c. PTZ) and 6-Hz (32 mA) test in mice. Therefore, AS-1 may be recognized candidate for new effective different types of human epilepsy with favorable safety margin profile determined rotarod aim further pharmacological evaluation AS-1, current study, examined its activity (44 is known model drug-resistant epilepsy. Furthermore, also antiseizure kindling induced by repeated injection (PTZ) As result, revealed relatively well delayed progression PTZ mice at doses 15 mg/kg, 30 60 mg/kg. Importantly, isobolographic analysis that combination valproic acid (VPA) fixed ratio 1:1 displayed supra-additive (synergistic) interaction against PTZ-induced seizures Thus, potentially used an add-on therapy VPA. Moreover, incubation zebrafish larvae substantially decreased number, cumulative but not mean duration epileptiform-like events electroencephalographic assay. Finally, vitro ADME-Tox studies characterized very good permeability parallel artificial membrane assay excellent metabolic stability on liver microsomes (HLMs), no significant influence CYP3A4/CYP2D6 activity, moderate inhibition CYP2C9 concentration 10 μM, hepatotoxic properties HepG2 cells (concentration μM).