Design, Synthesis and Antiinflammatory Activity of a New Indomethacin Ester. 2-[N-[3-{3-(Piperidinomethyl)phenoxy}propyl]carbamoylmethylthio]ethyl 1-(p-Chlorobenzoyl)-5-methoxy-2-methylindole-3-acetate

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 hing-paw edema in the rat at a very high dose of 230 mg/kg (280 μmol/kg), which is comparable to that of 100 mg/kg (280 μmol/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.