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.
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).
Velázquez
Carlos A
CA
Chemistry Section, Laboratory of Comparative Carcinogenesis and Basic Research Program, SAIC-Frederick Inc., National Cancer Institute at Frederick, MD 21702, USA.
Chen
Qiao-Hong
QH
Citro
Michael L
ML
Keefer
Larry K
LK
Knaus
Edward E
EE
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001241:Aspirin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001391:Azo Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002351:Carrageenan; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D007213:Indomethacin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009569:Nitric Oxide / Q000737:chemistry*; D020030:Nitric Oxide Donors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013276:Stomach Ulcer / Q000139:chemically induced
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001391:Azo Compounds; D020030:Nitric Oxide Donors; D011355:Prodrugs; D011759:Pyrrolidines; D009569:Nitric Oxide; D002351:Carrageenan; D001241:Aspirin; D007213:Indomethacin