2,4(5)-Diarylimidazoles as inhibitors of hNaV1.2 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 NaV1.2 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 D7.4) and basicity (pKa) 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 hNaV1.2 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.

The synthesis, biological evaluation for block of hNaV1.2 sodium channels and physico-chemical properties of a series of 2,4(5)-diarylimidazoles with different substituents on phenyl rings are described and discussed. The most active compound obtained inhibits hNaV1.2 currents within the nanomolar concentration range.Figure optionsDownload as PowerPoint slide