| Summary: | Background: Cenobamate is an antiseizure medication used to treat partial-onset (focal) seizures. It is a molecule with one chiral center and a unique dual mechanism of action: enhancement of fast and slow inactivation of sodium channels with preferential inhibition of the persistent current and positive allosteric modulation of GABAA receptor-mediated ion channels. Aims/Methods: Anticonvulsant effects of cenobamate (YKP3089; R-enantiomer), YKP3090 (S-enantiomer), and YKP1983 (racemate) were evaluated in chemically and electrically induced focal and generalized seizure models in rodents. The Genetic Absence Epilepsy Rat from Strasbourg (GAERS) model examined the effect of cenobamate on spike-wave seizures. Motor coordination was assessed with rotarod tests and minimal motor impairment exams. Results: Early in development, cenobamate was found to have activity in focal and generalized seizure models in animals and was selected for continued development. Cenobamate prevented seizures in a dose-dependent manner, prevented seizure spread, and increased seizure threshold without potentiating seizure initiation or the development of tolerance to its anticonvulsant effects. In contrast, YKP3090 and YKP1983 were only effective against generalized tonic-clonic seizures. Cenobamate also protected mice from 6 Hz psychomotor-induced seizures. Cenobamate showed significant dose-dependent reductions in the number and cumulative duration of spike-and-wave discharges in the GAERS model. Discussion: Cenobamate showed efficacy or efficacy signals in all animal models of epilepsy tested with a favorable risk-versus-benefit ratio, supporting its clinical use in the treatment of partial-onset (focal) seizures in adults and warranting further clinical research in generalized seizures and absence seizures.
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