Structure-activity relationships of (arylalkyl)imidazole anticonvulsants: comparison of the (fluorenylalkyl)imidazoles with nafimidone and denzimol

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Abstract
A recently discovered and structurally distinct class of antiepileptic drugs is the (arylalkyl)imidazoles. Two independently discovered representatives of this class, denzimol (.alpha.-[4-(2-phenylethyl)phenyl]-1H-imidazole-1-ethanol) and nafimidone (2-(1H-imidazol-1-yl)-(2-naphthalenyl)ethanone), are undergoing clinical evaluation. Our structure-activity relationship (SAR) studies revealed that in addition to the naphthalenyl and phenethylphenyl aryl moieties of nafimidone and denzimol, respectively, fluorenyl, benzo[b]thienyl, and benzofuranyl aryl groups provided several highly active (arylakyl)imidazole anticonvulsants. These structurally diverse aryl moieties, and comparable anticonvulsant activities, lend credence to the hypothesis that the pharmacophore of this class of anticonvulsants is the alkylimidazole portion of the molecule, with the lipophilic aryl portion enabling penetration of the blood-brain barrier. We focused our SAR studies on the (fluorenylalkyl)imidazole series. A representative compound from this series is 1-(9H-fluoren-2-yl)-2-(1H-imidazol-1-yl)ethanone (27). This agent was twice as potent as nafimidone in inhibiting maximal electroshock seizures in mice (po ED50''s = 25 and 56 mg/kg, respectively) and considerably less toxic in the rat (po LD50''s = 4550 and 504 mg/kg, respectively). The tertiary alcohol .alpha.-(9H-fluoren-2-yl)-.alpha.-methyl-1H-imidazole-1-ethanol (46) was as potent as denzimol in mice (po ED50''s = 10 and 12 mg/kg respectively). This series of imidazole anticonvulsants was highly selective; while many compounds displayed potent antielectroshock activity, little or no activity was observed against pentylenetetrazole-induced clonic seizures or in the horizontal screen test for ataxia. All active compounds that we tested in this series, as well as denzimol and nafimidone, potentiated hexobarbital-induced sleeping time in mice, probably by imidazole-mediated inhibition of cytochrome P-450. The SAR''s for the anticonvulsant activity and the sleeping time potentiation were similar. The propensity of these (arylalkyl)imidazole anticonvulsants to interact strongly with cytochrome P-450 and thereby impair the metabolism of other antiepileptic drugs may severely limit their clinical utility as anticonvulsants.