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.

Department of Drug Technology and Pharmaceutical Biotechnology Medical University of Warsaw Banacha 1 02 097 Warsaw Poland

Department of Drug Technology and Pharmaceutical Biotechnology Medical University of Warsaw Banacha 1 02 097 Warsaw Poland; Laboratory of Physiology and Pathophysiology Centre for Preclinical Research Medical University of Warsaw Banacha 1B 02 097 Warsaw Poland

Department of Experimental Physiology and Pathophysiology Centre for Preclinical Research Medical University of Warsaw Banacha 1B 02 097 Warsaw Poland

Department of Physiology Biomedical Center Faculty of Medicine in Pilsen Charles University Alej Svobody 1655 76 323 00 Pilsen Czech Republic

Institute of Structural Biology Helmholtz Zentrum München Ingolstädter Landstrasse 1 85764 Neuherberg Germany

School of Physiology Pharmacology and Neuroscience Faculty of Medical Sciences University of Bristol Bristol BS8 1TD United Kingdom

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