JavaScript NENÍ povolen !

* Zobrazit nápovědu

4 záznamů v Medvik Filtry

Článek

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

Dawidowski, Maciej
Autor Dawidowski, Maciej Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland. Electronic address: maciej.dawidowski@wum.edu.pl
Król, Marek
Autor Król, Marek Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland
Szulczyk, Bartłomiej
Autor Szulczyk, Bartłomiej 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
Chodkowski, Andrzej
Autor Chodkowski, Andrzej Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland
Podsadni, Piotr
Autor Podsadni, Piotr Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland
Konopelski, Piotr
Autor Konopelski, Piotr Department of Experimental Physiology and Pathophysiology, Centre for Preclinical Research, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland
Ufnal, Marcin
Autor Ufnal, Marcin Department of Experimental Physiology and Pathophysiology, Centre for Preclinical Research, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland
Szuberski, Piotr
Autor Szuberski, Piotr Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland
Wróbel, Martyna Zofia
Autor Wróbel, Martyna Zofia Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland
Zhang, Yihong
Autor Zhang, Yihong School of Physiology, Pharmacology and Neuroscience, Faculty of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom

Bioorganic chemistry. 2020 ; 98 (-) : 103717. [pub] 20200305

Bioorg Chem
ISSN 1090-2120
Medvik
Zdroj

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.