NSAID Prodrugs with Improved Anti-inflammatory Activity and Low Ulcerogenicity: Wake Up Call to Pharmaceutical Companies and Health Authorities

The objective of this work was to synthesize and evaluate the biological properties of a new series of nitric oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) possessing a tyrosol linker between the carboxylic acid present in classical NSAIDs and a NO-releasing group (PROLI/NO) derived from the naturally occurring amino acid L-proline; however, initial screening of ester intermediates without the PROLI/NO group showed the desired efficacy/safety ratio. The NSAID prodrugs were potent selective COX-2 inhibitors and showed equipotent anti-inflammatory activity compared to the corresponding parent NSAIDs, but showed a markedly reduced gastric toxicity. Furthermore, simple NSAID ester prodrugs were able to increase the activity of phase II carcinogen-metabolizing enzymes (NQO1); however, unlike NCX-4016 (NO-aspirin), NSAID esters were not effective inhibitors of platelet aggregation. These results provide complementary evidence to assume that the use of NO-releasing groups in hybrid NSAID prodrugs is not required to decrease the ulcerogenic profile of classical NSAIDs.