A pharmacophore derived phenytoin analogue with increased affinity for slow inactivated sodium channels exhibits a desired anticonvulsant profile

In the 6 Hz seizure model (32 mA) HA had an ED50 of 47.1 mg/kg and a TD50 of 131 mg/kg (protective index (PI) = 2.8). In comparison, the ED50 for DPH was ∼27.5 mg/kg with a TD50 of 35.6 mg/kg (PI ∼ 1.3). These findings provide evidence for the utility of CoMFA in the design of novel anticonvulsants and support the hypothesis that states selectivity plays an important role in achieving optimal protection with minimal side effects.