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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Anti-Inflammatory Agents, Non-Steroidal / toxicity*
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Aspirin / analogs & derivatives
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Aspirin / chemical synthesis
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Aspirin / pharmacology
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Aspirin / toxicity
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Binding Sites
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Cyclooxygenase 1 / chemistry
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Cyclooxygenase 2 / chemistry
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Cyclooxygenase Inhibitors / chemical synthesis
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Cyclooxygenase Inhibitors / pharmacology
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Cyclooxygenase Inhibitors / toxicity
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Edema / drug therapy
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Humans
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Ibuprofen / analogs & derivatives
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Ibuprofen / chemical synthesis
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Ibuprofen / pharmacology
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Ibuprofen / toxicity
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Indomethacin / analogs & derivatives
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Indomethacin / chemical synthesis
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Indomethacin / pharmacology
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Indomethacin / toxicity
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Nitric Oxide / metabolism*
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Nitric Oxide Donors / chemical synthesis
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Nitric Oxide Donors / pharmacology
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Nitric Oxide Donors / toxicity*
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Peptic Ulcer / chemically induced*
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Phenylethyl Alcohol / chemistry
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Prodrugs / chemical synthesis
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Prodrugs / pharmacology
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Prodrugs / toxicity*
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Rats
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / chemistry
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Structure-Activity Relationship
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Cyclooxygenase Inhibitors
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Nitric Oxide Donors
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Prodrugs
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Recombinant Proteins
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Nitric Oxide
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Cyclooxygenase 1
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Cyclooxygenase 2
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Phenylethyl Alcohol
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Aspirin
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Ibuprofen
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Indomethacin