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

J Med Chem. 2008 Mar 27;51(6):1954-61. doi: 10.1021/jm701450q. Epub 2008 Feb 29.

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).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Aspirin / chemical synthesis
  • Aspirin / chemistry
  • Aspirin / pharmacology*
  • Azo Compounds / chemical synthesis
  • Azo Compounds / chemistry
  • Azo Compounds / pharmacology*
  • Carrageenan
  • Drug Design
  • Edema / chemically induced
  • Edema / drug therapy
  • Indomethacin / chemical synthesis
  • Indomethacin / chemistry
  • Indomethacin / pharmacology*
  • Molecular Structure
  • Nitric Oxide / chemistry*
  • Nitric Oxide Donors / chemical synthesis
  • Nitric Oxide Donors / chemistry
  • Nitric Oxide Donors / pharmacology*
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry
  • Prodrugs / pharmacology*
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology*
  • Rats
  • Stomach Ulcer / chemically induced

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Azo Compounds
  • Nitric Oxide Donors
  • Prodrugs
  • Pyrrolidines
  • Nitric Oxide
  • Carrageenan
  • Aspirin
  • Indomethacin