title: Novel nonsteroidal antiinflammatory drugs possessing a nitric oxide donor diazen-1-ium-1,2-diolate moiety: design, synthesis, biological evaluation, and nitric oxide release studies.
abstract: A novel group of hybrid nitric oxide-releasing nonsteroidal antiinflammatory drugs ((*)NO-NSAIDs) possessing a 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (11, 13, 15) or 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (12, 14, 16) moiety attached via a one-carbon methylene spacer to the carboxylic acid group of the traditional NSAIDs aspirin, ibuprofen, and indomethacin were synthesized. Although none of these ester prodrugs (11-16) exhibited in vitro cyclooxygenase (COX) inhibitory activity against the COX-1 and COX-2 isozymes (IC(50) > 100 microM), all of the compounds (11-16) significantly decreased carrageenan-induced rat paw edema. In this regard, the ester prodrugs 11-16 showed equipotent antiinflammatory activities in vivo to that of the parent drugs aspirin, ibuprofen, and indomethacin. All of the compounds released nitric oxide upon incubation with either phosphate buffer solution at pH 7.4 (14-16% range) or porcine liver esterase (16-19% range), but the percentage of (*)NO released was up to sixfold higher (93%) when these ester prodrugs were incubated with guinea pig serum. These incubation studies suggest that both (*)NO and the parent NSAID would be released upon in vivo cleavage by nonspecific serum esterases. The simultaneous release of aspirin and nitric oxide from the (*)NO-aspirin prodrugs constitutes a potentially beneficial property for the prophylactic prevention of thrombus formation and adverse cardiovascular events such as stroke and myocardial infarction. The data acquired in an in vivo ulcer index (UI) assay showed that for this group of ester prodrugs, particularly the (*)NO-aspirins (11, 12) and (*)NO-ibuprofens (13, 14), no lesions were observed (UI = 0) when compared to the parent drugs aspirin (UI = 57, 250 mg/kg po dose), ibuprofen (UI = 45, 250 mg/kg po dose), or indomethacin (UI = 34, 30 mg/kg po dose) at equivalent doses. Accordingly, these hybrid (*)NO-NSAID prodrugs possessing a diazen-1-ium-1,2-diolate moiety, represent a new approach for the rational design of antiinflammatory drugs with reduced gastric ulcerogenicity.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
authors.forename: Carlos
authors.initials: C
authors.lastname: Velázquez
authors.forename: P N
authors.initials: PN
authors.lastname: Praveen Rao
authors.forename: Edward E
authors.initials: EE
authors.lastname: Knaus
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D001241:Aspirin / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry; D001391:Azo Compounds / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology; D004952:Esters / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology; D006168:Guinea Pigs; D007052:Ibuprofen / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry; D066298:In Vitro Techniques; D007213:Indomethacin / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry; D008565:Membrane Proteins; D009569:Nitric Oxide / Q000737:chemistry / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D011355:Prodrugs / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry; D011759:Pyrrolidines / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013276:Stomach Ulcer / Q000139:chemically induced; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001391:Azo Compounds; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004952:Esters; D008565:Membrane Proteins; D020030:Nitric Oxide Donors; D011355:Prodrugs; D011759:Pyrrolidines; D009569:Nitric Oxide; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D001241:Aspirin; D007052:Ibuprofen; D007213:Indomethacin