title: 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-methyl-indole-3-acetate.
abstract: 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.
authors.affiliation: Institute of Scientific and Industrial Research, Osaka University, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Ueda
authors.forename: K
authors.initials: K
authors.lastname: Ishii
authors.forename: H
authors.initials: H
authors.lastname: Arai
authors.forename: S
authors.initials: S
authors.lastname: Ikeda
authors.forename: Y
authors.initials: Y
authors.lastname: Hitomi
authors.forename: M
authors.initials: M
authors.lastname: Hatanaka
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology; D007213:Indomethacin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011355:Prodrugs; C069844:CP 331; D007213:Indomethacin