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

Phenytoin (DPH) is a clinically useful sodium (Na) channel blocker with efficacy against partial and generalized seizures. We have developed a novel hydantoin compound (HA) using comparative molecular field analysis (CoMFA) and evaluated its effects on hNa_v1.2 channels. Both DPH and HA demonstrated affinity for resting (K_r = 13.9 μM for HA, K_r = 464 μM for DPH) and slow inactivated channels (K_I = 975 nM for HA, K_I = 20.6 μM for DPH). However, HA also exhibited an affinity for fast inactivated channels (K_I = 2.5 μM) and shifted the V_1/2 for activation in the depolarizing direction. Furthermore, HA exhibited profound use dependent block at both 5 and 10 Hz stimulation frequencies. 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.