Ethanesulfohydroxamic Acid Ester Prodrugs of Nonsteroidal Anti-inflammatory Drugs (NSAIDs): Synthesis, Nitric oxide and Nitroxyl Release, Cyclooxygenase Inhibition, Anti-inflammatory, and Ulcerogenici

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• 作者：Zhangjian Huang ; Carlos A. Vela虂zquez ; Khaled R. A. Abdellatif ; Morshed A. Chowdhury ; Julie A. Reisz ; Jenna F. DuMond ; S. Bruce King ; Edward E. Knaus
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：March 10, 2011
• 年：2011
• 卷：54
• 期：5
• 页码：1356-1364
• 全文大小：862K
• 年卷期：v.54,no.5(March 10, 2011)
• ISSN：1520-4804

文摘

The carboxylic acid group of the anti-inflammatory (AI) drugs indo-methacin, (S)-naproxen and ibuprofen was covalently linked via a two-carbon ethyl spacer to a sulfohydroxamic acid moiety (CH₂CH₂SO₂NHOH) to furnish a group of hybrid ester prodrugs that release nitric oxide (NO) and nitroxyl (HNO). Biological data acquired for this hitherto unknown class of ethanesulfohydroxamic acid ester prodrugs showed (i) all compounds exhibited superior NO, but similar HNO, release properties relative to arylsulfohydroxamic acids, (ii) the (S)-naproxen and ibuprofen prodrug esters are more potent AI agents than their parent NSAID, (iii) the indomethacin prodrug ester, in contrast to indomethacin which is highly ulcerogenic, showed no visible stomach lesions [ulcer index (UI) = 0 for a 80 渭mol/kg oral dose] while retaining potent AI activity, and iv) that the indomethacin prodrug ester, unlike indomethacin which is an ulcerogenic selective COX-1 inhibitor, is a selective COX-2 inhibitor (COX-2 selectivity index = 184) devoid of ulcerogenicity that is attributed to its high COX-2 SI and/or ability to release cytoprotective NO.