Buckle D R, Foster K A, Taylor J F, Tedder J M, Thody V E, Webster R A, Bermudez J, Markwell R E, Smith S A
Beecham Pharmaceuticals--Research Division, Biosciences Research Centre, Epsom, Surrey, England.
J Med Chem. 1987 Dec;30(12):2216-21. doi: 10.1021/jm00395a007.
The synthesis and structure--activity profile of 2-substituted benzimidazol-4-ols as inhibitors of cell-free RBL-1 5-lipoxygenase are discussed, and their potency is compared with that of the standard inhibitors phenidone, AA 861, BW 755C, and nordihydroguaiaretic acid. In contrast to the standard compounds, most did not inhibit the release of slow-reacting substance of anaphylaxis (SRS-A) in vivo when administered at 200 microM ip to rats subjected to peritoneal anaphylaxis, although five compounds containing a methoxylated benzyl group (compounds 36, 39, 42, and 43) or hydroxylated benzyl group (41) showed similar activity to that of phenidone, nordihydroguaiaretic acid, and AA 861. Of the many compounds tested, two, 5-tert-butyl-7-methyl-2-(trifluoromethyl)-1H-benzimidazol-4-ol (57) and 2-(4-methoxybenzyl)-7-methyl-1H-benzimidazol-4-ol (36), like dexamethasone, inhibited monocyte accumulation in a pleural exudate model of inflammation. Standard lipoxygenase inhibitors such as phenidone, BW 755C, and AA 861 were inactive in this system.
讨论了2-取代苯并咪唑-4-醇作为无细胞RBL-1 5-脂氧合酶抑制剂的合成及其构效关系，并将它们的效力与标准抑制剂非那宗、AA 861、BW 755C和去甲二氢愈创木酸进行了比较。与标准化合物不同的是，大多数化合物在以200微摩尔/千克腹腔注射给腹膜过敏反应的大鼠时，在体内并不抑制过敏反应慢反应物质（SRS-A）的释放，尽管含有甲氧基苄基（化合物36、39、42和43）或羟基苄基（41）的五种化合物表现出与非那宗、去甲二氢愈创木酸和AA 861相似的活性。在测试的许多化合物中，两种化合物，即5-叔丁基-7-甲基-2-（三氟甲基）-1H-苯并咪唑-4-醇（57）和2-（4-甲氧基苄基）-7-甲基-1H-苯并咪唑-4-醇（36），与地塞米松一样，在炎症的胸腔渗出液模型中抑制单核细胞积聚。标准脂氧合酶抑制剂如非那宗、BW 755C和AA 861在该系统中无活性。
