A Novel Series of (Phenoxyalkyl)imidazoles as Potent H3-Receptor Histamine Antagonists†

[[(4-Nitrophenyl)X]alkyl]imidazole isosteres (where X = NH, S, CH 2 S, 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 [ 3 H]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]-lH-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 [(aryloxyethyl]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).