Second-Generation Aspirin and Indomethacin Prodrugs Possessing an O2-(Acetoxymethyl)-1-(2-carboxypyrrolidin-1-yl)diazenium-1,2-diolate Nitric Oxide Donor Moiety: Design, Synthesis, B

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• 作者：Carlos A. Velá ; zquez ; Qiao-Hong Chen ; Michael L. Citro ; Larry K. Keefer ; Edward E. Knaus
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：March 27, 2008
• 年：2008
• 卷：51
• 期：6
• 页码：1954 - 1961
• 全文大小：173K
• 年卷期：v.51,no.6(March 27, 2008)
• ISSN：1520-4804

文摘

The carboxylic acid group of the anti-inflammatory (AI) drugs aspirin and indomethacin was covalently linked to the 1-(2-carboxypyrrolidin-1-yl)diazen-1-ium-1,2-diolate ion via a one-carbon methylene spacer to obtain two new hybrid prodrugs. The aspirin prodrug (23) was a 2.2-fold more potent AI agent than aspirin, whereas the indomethacin prodrug (26) was about 1.6-fold less potent than indomethacin. Prodrugs 23 and 26 slowly released nitric oxide (NO) upon dissolution in phosphate buffer at pH 7.4 (1.1 mol of NO/mol of compound after 43 h), but the rate and the extent of NO release were higher (1.9 mol of NO/mol of compound in 3 min or less) when the compounds were incubated in the presence of porcine liver esterase. In vivo ulcer index (UI) studies showed that the aspirin prodrug 23 (UI = 0.7) and indomethacin prodrug 26 (UI = 0) were substantially less ulcerogenic than the parent drugs aspirin (UI = 51) and indomethacin (UI = 64).