Hyperexcited neuronal voltage-gated sodium channels (VGSCs) play a key role in seizure activity, a characteristic symptom of epilepsy. The state dependent inhibition of these hyperexcited VGSCs is both advantageous and possible with phenytoin (IC₅₀ 40 μM) and other imidazolidine-2,4-dione analogs. The two analogous structural classes were developed using Comparative Molecular Field Analysis (CoMFA) to effectively bind to the VGSC anticonvulsant binding site. For the series of targeted VGSC inhibitors CoMFA predicted that increased hydrophobicity in the aliphatic side chain should provide for increased inhibition of the neuronal VGSCs. The synthesis of the predicted compounds, with IC₅₀ values between 3.6 and 22.5 μM, is presented.