Tanaka M, Chiba K, Okita M, Kaneko T, Tagami K, Hibi S, Okamoto Y, Shirota H, Goto M, Obaishi H
Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
J Med Chem. 1992 Dec 11;35(25):4665-75. doi: 10.1021/jm00103a003.
A new series of 3-(4-hydroxy-1-naphthalenyl)-2-propenoic acids was prepared and the inhibitory activities of its members on IL-1 generation were evaluated both by in vitro systems using human monocytes and/or rat exudated macrophages stimulated with LPS, and by an in vivo system using the rat CMC-LPS air-pouch model. Many compounds in this series were found to be potent inhibitors of IL-1 generation both in vitro and in vivo. Structure-activity relationships indicated that in the rat CMC-LPS air-pouch model by oral administration the (Z)-2-substituted propenoic acids with 3-alkoxy, 5-alkyl, and 4-hydroxy substituents on the naphthalene ring exhibit optimal inhibition. Among the compounds evaluated, (Z)-3-(5-ethyl-4-hydroxy-3-methoxy-1-naphthalenyl)-2-methyl-2-propeno ic acid (20a), which inhibited IL-1 generation from human monocytes with an IC50 value of 3.0 microM and had an IC50 value of 1.4 microM for rat exudated macrophages, showed the most potent inhibitory activity in the rat CMC-LPS model by oral administration. Compound 20a also showed antiinflammatory effects in animal models of inflammation.
制备了一系列新的3-(4-羟基-1-萘基)-2-丙烯酸，并通过使用人单核细胞和/或经脂多糖刺激的大鼠渗出巨噬细胞的体外系统以及使用大鼠CMC-LPS气袋模型的体内系统，评估了其成员对白细胞介素-1生成的抑制活性。发现该系列中的许多化合物在体外和体内都是白细胞介素-1生成的有效抑制剂。构效关系表明，在大鼠CMC-LPS气袋模型中通过口服给药，萘环上具有3-烷氧基、5-烷基和4-羟基取代基的(Z)-2-取代丙烯酸表现出最佳抑制作用。在所评估的化合物中，(Z)-3-(5-乙基-4-羟基-3-甲氧基-1-萘基)-2-甲基-2-丙烯酸(20a)，其对人单核细胞白细胞介素-1生成的抑制中浓度(IC50)值为3.0微摩尔，对大鼠渗出巨噬细胞的IC50值为1.4微摩尔，在大鼠CMC-LPS模型中口服给药时显示出最有效的抑制活性。化合物20a在炎症动物模型中也显示出抗炎作用。
