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 (wh ere X = NH, S) have been synthesized and evaluated for H-3-receptor hi stamine antagonism in vitro (K-i for [H-3]histamine release from rat c erebral cortex synaptosomes) and in vivo (ED(50) per os in mice on bra in tele-methylhistamine levels). Encouraging results led to the synthe sis 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 ca ndidates for drug development, For 16 [(aryloxy)ethyl]imidazoles the r elationship between in vitro and in vivo potency is described by the e quation log ED(50) - 0.47 log K-i + 0.20 (r = 0.78).