Ueda I, Ishii K, Arai H, Ikeda S, Hitomi Y, Hatanaka M
Institute of Scientific and Industrial Research, Osaka University, Japan.
Chem Pharm Bull (Tokyo). 1991 Mar;39(3):679-84. doi: 10.1248/cpb.39.679.
A novel indomethacin ester prodrug, 2-[N-[3-(3-(piperidinomethyl)phenoxy)propyl]carbamoylmethylthio ]ethyl 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetate (1) was prepared from a new histamine H2-receptor antagonist, N-[3-(3-(piperidinomethyl)phenoxy)propyl]-2-(2-hydroxyethylthio )acetamide (2) and indomethacin (3). The compound 1 was shown to be essentially similar to 3 in its antiinflammatory action and to almost completely inhibit carrageenin-induced hind-paw edema in the rat at a very high dose of 230 mg/kg (280 mumol/kg), which is comparable to that of 100 mg/kg (280 mumol/kg) of 3, without producing gastric lesions. On a molar basis, the acute gastric lesioning properties of 1 were near one-hundred times less than those of 3, resulting in over a twenty-fold improvement in the ratio of antiedema activity to ulcerogenicity. The effect of the co-administration of histamine H2-receptor antagonists on antiedema activity and ulcerogenicity caused by 3 is also discussed.
一种新型吲哚美辛酯前药，2-[N-[3-(3-(哌啶甲基)苯氧基)丙基]氨基甲酰甲基硫代]乙基 1-(对氯苯甲酰基)-5-甲氧基-2-甲基吲哚-3-乙酸酯(1)，由一种新型组胺H2受体拮抗剂N-[3-(3-(哌啶甲基)苯氧基)丙基]-2-(2-羟乙基硫代)乙酰胺(2)和吲哚美辛(3)制备而成。化合物1在抗炎作用方面与3基本相似，在230 mg/kg(280 μmol/kg)的非常高剂量下几乎能完全抑制角叉菜胶诱导的大鼠后爪水肿，这与3的100 mg/kg(280 μmol/kg)相当，且不会产生胃部损伤。以摩尔为基础，1的急性胃损伤特性比3低近一百倍，导致抗水肿活性与致溃疡活性的比值提高了二十多倍。还讨论了组胺H2受体拮抗剂联合给药对3引起的抗水肿活性和致溃疡性的影响。
