Discovery of triazenyl triazoles as Na_v1.1 channel blockers for treatment of epilepsy

The voltage-gated sodium (Nav) channel is one of most important targets for treatment of epilepsy, and rufinamide is an approved third-generation anti-seizure drug as Na(v)1.1 channel blocker. Herein, by triazenylation of rufinamide, we reported the triazenyl triazoles as new Na(v)1.1 channel blocker for treatment of epilepsy. Through the electrophysiological activity assay, compound 6a and 6e were found to modulate the inactivation voltage of Na-v 1.1 channel with shift of-10.07 mv and-11.28 mV, respectively. In the pentylenetetrazole (PTZ) mouse model, 6a and 6e reduced the seizure level, prolonged seizure latency and improved the survival rate of epileptic mice at an intragastric administration of 50 mg/kg dosage. In addition, 6a also exhibited promising effectiveness in the maximal electroshock (MES) mouse model and possessed moderate pharmacokinetic profiles. These results demonstrated that 6a was a novel Na(v)1.1 channel blocker for treatment of epilepsy.