2,4(5)-Diarylimidazoles as inhibitors of hNa_V1.2 sodium channels: Pharmacological evaluation and structure-property relationships

Sodium (Na) channels continue to represent an important target for the development of novel anticonvulsants. We have synthesized and evaluated a series of 2,4(5)-diarylimidazoles for inhibition of the human neuronal Na_V1.2 Na channel isoform. Starting with the unsubstituted lead compound previously published 3, SAR studies were performed introducing substituents with different physico-chemical properties. Lipophilicity (log D_7.4) and basicity (pK_a) of the compounds were measured and submitted for QSPR investigations. Some of the active compounds described had IC₅₀ values that were considerably lower than our lead compound. In particular, the m-CF₃ disubstituted 22 was the most active compound, inhibiting hNa_V1.2 currents within the nanomolar concentration range (IC₅₀ = 200 nM). In comparison, lamotrigine and phenytoin, two clinically used anticonvulsant drugs known to inhibit Na channels, had IC₅₀'s values that were greater than 100 μM.