Ganellin C R, Fkyerat A, Bang-Andersen B, Athmani S, Tertiuk W, Garbarg M, Ligneau X, Schwartz J C
Department of Chemistry, Christopher Ingold Laboratories, University College London, UK.
J Med Chem. 1996 Sep 13;39(19):3806-13. doi: 10.1021/jm960138l.
[[(4-Nitrophenyl)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 H3-receptor histamine antagonism in vitro (Ki for [3H]histamine release from rat cerebral cortex synaptosomes) and in vivo (ED50 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; Ki = 12 nM, ED50 = 0.54 mg/kg) and 4-[3-[4-(trifluoromethyl)-phenoxy]propyl]-1H-imidazole (10c, UCL 1409; Ki = 14 nM, ED50 = 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 ED50 = 0.47 log Ki + 0.20 (r = 0.78).
已合成了先前描述的[[(5-硝基吡啶-2-基)X]乙基]咪唑（其中X = NH、S）的[[(4-硝基苯基)X]烷基]咪唑生物电子等排体（其中X = NH、S、CH₂S、O），并对其进行了体外（大鼠大脑皮层突触体中[³H]组胺释放的Ki值）和体内（小鼠口服对脑内甲基组胺水平的ED50）H₃受体组胺拮抗作用评估。令人鼓舞的结果促使合成并测试了一系列新型的取代（苯氧乙基）-和（苯氧丙基）咪唑。从后者中，4-[3-(4-氰基苯氧基)丙基]-1H-咪唑（10a，UCL 1390；Ki = 12 nM，ED50 = 0.54 mg/kg）和4-[3-[4-(三氟甲基)苯氧基]丙基]-1H-咪唑（10c，UCL 1409；Ki = 14 nM，ED5 = 0.60 mg/kg）已被选为药物开发的潜在候选物。对于16种[(芳氧基)乙基]咪唑，体外和体内效价之间的关系由方程log ED50 = 0.47 log Ki + 0.20（r = 0.78）描述。
