Structure-activity relationship and cardiac safety of 2-aryl-2-(pyridin-2-yl)acetamides, and new class of broad-spectrum anticonvulsants derived from Disopyramide
Abstrakt
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, in contrast to the parent compound, a representative of this series displays high levels of cardiac safety in a panel of in vitro and in vivo experiments.