Imidazole Anticonvulsants: Structure-Activity Relationships of imidazoles

Article abstract of DOI:10.1021/jm00388a035

The <(biphenylyloxy)alkyl>imidazoles were found to be potent anticonvulsants.The most potent compound of the series, 1-<2-(<1,1'-biphenyl>-2-yloxy)ethyl>-1H-imidazole (4), had an ED₅₀ of 15.5 mg/kg aggainst maximal-electroshock-induced seizures in mice after oral administration; the horizontal screen ED₅₀ was 320 mg/kg, revealing that the compound has a protective index of 21.Homologues bearing three- and four-carbon tethers between the imidazole and biphenylyloxy moieties were also active, but their potency was attenuated relative to 4.Congeners with the imidazolyalkoxy moiety at the meta or para positions of biphenyl were also less active.All these compounds were potent potentiators of hexobarbital-induced sleeping time in mice, presumably via the well-known imidazole-mediated inhibition of cytochrome P-450.The structural features governing the anticonvulsant and sleeping-time activities appear to be distinct, but a complete dissociation of these two effects has not been achieved.Thus, the potential of these compounds as clinically useful antiepileptic drugs would appear to be limited.