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Second-generation aspirin and indomethacin prodrugs possessing an O-2-(Acetoxymethyl)-1-(2-carboxypyrrolidin-1-yl)diazenium-1,2-diolate nitric oxide donor moiety: Design, synthesis, biological evaluation, and nitric oxide release studies

  1. Author:
    Velazquez, C. A.
    Chen, Q. H.
    Citro, M. L.
    Keefer, L. K.
    Knaus, E. E.

  2. Author Address

    Chen, Qiao-Hong, Knaus, Edward E.] Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2N8, Canada. [Velazquez, Carlos A.; Keefer, Larry K.] NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. [Citro, Michael L.] NCI, SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA.
    1. Year: 2008
  2. Journal: Journal of Medicinal Chemistry
    1. 51
    2. 6
    3. Pages: 1954-1961
  4. Type of Article: Article
  1. Abstract:

    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).

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External Sources

  1. PMID: 18314945

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