O2-acetoxymethyl-protected diazeniumdiolate-based NSAIDs (NONO-NSAIDs): synthesis, nitric oxide release, and biological evaluation studies.
A novel group of O2-acetoxymethyl-protected diazeniumdiolate-based non-steroidal anti-inflammatory prodrugs (NONO-NSAIDs) were synthesized by esterifying the carboxylate group of aspirin, ibuprofen, or indomethacin with O2-acetoxymethyl 1-[N-(2-hydroxyethyl)-N-methylamino]diazeniumdiolate. The resulting nitric oxide (*NO)-releasing prodrugs (7-9) did not exhibit in vitro cyclooxygenase (COX) inhibitory activity against the COX-1 and COX-2 isozymes (IC50s>100 microM). In contrast, prodrugs 7 and 8 significantly decreased carrageenan-induced rat paw edema showing enhanced in vivo anti-inflammatory activities (ID50's=552 and 174 micromol/kg, respectively) relative to those of the parent NSAIDs aspirin (ID50=714 micromol/kg) and ibuprofen (ID50=326 micromol/kg). The rate of porcine liver esterase-mediated *NO release from prodrugs 7-9 (2 mol of *NO/mol of test compound in 0.6-6.5 min) was substantially higher compared to that observed without enzymatic catalysis (about 1 mol of *NO/mol of test compound in 40-48 h). These incubation studies suggest that both *NO and the parent NSAID would be released upon in vivo activation (hydrolysis) by esterases. Data acquired in an in vivo ulcer index (UI) assay showed that NONO-aspirin (UI=0.8), NONO-indomethacin (UI=1.3), and particularly NONO-ibuprofen (UI=0) were significantly less ulcerogenic compared to the parent drugs aspirin (UI=57), ibuprofen (UI=46) or indomethacin (UI=34) at equimolar doses. The release of aspirin and *NO from the NONO-aspirin (7) prodrug constitutes a potentially beneficial property for the prophylactic prevention of thrombus formation and adverse cardiovascular events such as stroke and myocardial infarction.
Velázquez
Carlos A
CA
Chemistry Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
Praveen Rao
P N
PN
Citro
Michael L
ML
Keefer
Larry K
LK
Knaus
Edward E
EE
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D008745:Methylation; D015394:Molecular Structure; D009569:Nitric Oxide / Q000737:chemistry* / Q000378:metabolism*; D019301:Oleic Acid / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D010100:Oxygen / Q000737:chemistry*; D051381:Rats; D012756:Sheep; D013276:Stomach Ulcer / Q000188:drug therapy / Q000473:pathology; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D019301:Oleic Acid; D009569:Nitric Oxide; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D010100:Oxygen