title: Nitric oxide release is not required to decrease the ulcerogenic profile of nonsteroidal anti-inflammatory drugs.
abstract: The objective of this work was to evaluate the biological properties of a new series of nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NO-NSAIDs) possessing a tyrosol linker between the NSAID and the NO-releasing moiety (PROLI/NO); however, initial screening of ester intermediates without the PROLI/NO group showed the required (desirable) efficacy/safety ratio, which questioned the need for NO in the design. In this regard, NSAID ester intermediates were potent and selective COX-2 inhibitors in vitro, showed equipotent anti-inflammatory activity compared to the corresponding parent NSAID, but showed a markedly reduced gastric toxicity when administered orally. These results provide complementary evidence to challenge the currently accepted notion that hybrid NO-NSAIDs exert their cytoprotective effects by releasing NO. Results obtained in this work constitute a good body of evidence to initiate a debate about the future replacement of NSAID prodrugs for unprotected NSAIDs (possessing a free carboxylic acid group) currently in clinical use.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2N8 Canada.
authors.forename: Sarthak
authors.initials: S
authors.lastname: Jain
authors.forename: Susan
authors.initials: S
authors.lastname: Tran
authors.forename: Mohamed A M
authors.initials: MA
authors.lastname: El Gendy
authors.forename: Khosrow
authors.initials: K
authors.lastname: Kashfi
authors.forename: Paul
authors.initials: P
authors.lastname: Jurasz
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Velázquez-Martínez
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D001241:Aspirin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D001665:Binding Sites; D051545:Cyclooxygenase 1 / Q000737:chemistry; D051546:Cyclooxygenase 2 / Q000737:chemistry; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D004487:Edema / Q000188:drug therapy; D006801:Humans; D007052:Ibuprofen / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D007213:Indomethacin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity*; D010437:Peptic Ulcer / Q000139:chemically induced*; D010626:Phenylethyl Alcohol / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity*; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D020030:Nitric Oxide Donors; D011355:Prodrugs; D011994:Recombinant Proteins; D009569:Nitric Oxide; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D010626:Phenylethyl Alcohol; D001241:Aspirin; D007052:Ibuprofen; D007213:Indomethacin