A novel series of (phenoxyalkyl)imidazoles as potent H-3-receptor histamine antagonists

[[(4-Nitrophenyll)X]alkyl]imidazole isosteres (where X = NH, S, CH2S, O) of previously described [[(5-nitropyrid-2-yl)X]ethyl]imidazoles (where X = NH, S) have been synthesized and evaluated for H-3-receptor histamine antagonism in vitro (K-i for [H-3]histamine release from rat cerebral cortex synaptosomes) and in vivo (ED(50) per os in mice on brain tele-methylhistamine levels). Encouraging results led to the synthesis and testing of a novel series of substituted (phenoxyethyl)- and (phenoxypropyl)imidazoles. From the latter, 4-[3-(4-cyanophenoxy)propyl]-1H-imidazole (10a, UCL 1390; K-i = 12 nM, ED(50) = 0.54 mg/kg) and 4-[3-[4-(trifluoromethyl)-- phenoxy]propyl]-1H-imidazole (10c, UCL 1409; K-i = 14 nM, ED(50) = 0.60 mg/kg) have been selected as potential candidates for drug development, For 16 [(aryloxy)ethyl]imidazoles the relationship between in vitro and in vivo potency is described by the equation log ED(50) - 0.47 log K-i + 0.20 (r = 0.78).