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

• Author / Creator

  Jain, Sarthak

• 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.

• Subjects / Keywords

  • NSAIDs
  • Nitric Oxide
  • Tyrosol
  • Gastric toxicity
  • Ulcerogenicity

• Graduation date

  Spring 2012

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/R3WT06

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.