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

Maciej Dawidowski, Marek Król, Bartłomiej Szulczyk, Andrzej Chodkowski, Piotr Podsadni, Piotr Konopelski, Marcin Ufnal, Piotr Szuberski, Martyna Zofia Wróbel, Yihong Zhang, Aziza El Harchi, Jules C Hancox, Dagmar Jarkovska, Eliska Mistrova, Jitka Sviglerova, Milan Štengl, Grzegorz M Popowicz, Jadwiga Turło

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Abstract

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.

Original languageEnglish
Article number103717
Number of pages14
JournalBioorganic chemistry
Volume98
Early online date5 Mar 2020
DOIs
Publication statusPublished - 1 May 2020

Keywords

  • voltage-gated sodium channel
  • sodium channel blocker
  • disopyramide
  • drug discovery
  • structure-activity relationships
  • anticonvulsant agent
  • refractory epilepsy
  • drug repositioning
  • medicinal chemistry
  • cardiac safety

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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. (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, 98, [103717]. https://doi.org/10.1016/j.bioorg.2020.103717