Nitric oxide NSAIDs

HCT-1026 (nitwflurbipwfen) is a nitric oxide-donating derivative of the NSAID flurbiprofen. It is undergoing Phase 1 clinical evaluation for the treatment of Alzheimer disease, but it is more advanced (Phase 11) for overactive bladder and osteoporosis. 

Flurbiprofen is a propionic acid derivative with a possibly more complex mechanism of action than other NSAIDs. Its (S)( ) enantiomer inhibits COX nonselectively, but it has been shown in rat tissue to also affect tumor necrosis factor- (TNF- ) and nitric oxide synthesis. Flepatic metabolism is extensive its (R) +) and (S) ) enantiomers are metabolized differently, and it does not undergo chiral conversion. It does demonstrate enterohepatic circulation. 

Berg, J., Fellier, H., Christoph, T., Grarup, J., Stimmeder, D. The analgesic NSAID lornoxicam inhibits cyclooxygenase (COX)-1/-2, inducible nitric oxide synthase (iNOS), and the formation of interleukin (IL)-6 in vitro, Inflamm. Res. 1999, 48, 369-79. 

More than 100 NSAIDs are marketed or at an advanced stage of development worldwide. Their use is constantly expanding and the search for more efficacious and better-tolerated compounds is still being pursued, and has received renewed impulse with studies on selective inhibitors of cyclo-oxygenase type 2 (COX-2), nitric oxide-releasing NSAIDs, peroxidase inhibitors, enantiomers of already known NSAIDs, NSAIDs associated with zwitterionic phospholipids, and cytokine-modulating antirheumatic drugs. 

Dunlap, T, Abdul-Hay, S.O., Chandrasena, R.E., Hagos, G.K., Sinha, V., Wang, Z., Wang, H., and Thatcher, G.R. (2008). Nitrates and no-nsaids in cancer chemoprevention and therapy In vitro evidence querying the no donor functionality. Nitric Oxide 19, 115-124. 

Rigas, B. and Kashli, K. (2004). Nitric-oxide-donating nsaids as agents for cancer prevention. Trends Mol. Med. 10, 324-330. 

Keywords Cancer biology Cancer chemoprevention Furoxans Nitric oxide releasing molecule (NORM) NONOate NO-NSAID Quinone methide... 

Fabbri, F, Biigliadoii, G., Ulivi, P., Tesei, A., Vannini, I., Rosetti, M., Bravaccini, S., Amadori, D., BoUa, M., and Zoli, W. (2005). Pro-apoptotic effect of a nitric oxide-donating Nsaid, Ncx 4040, on bladder carcinoma cells. Apoptosis 10, 1095-1103. 

Rigas, B. and Williams, J.L. (2008). No-donating nsaids and cancer An overview with a note on whether No is required for their action. Nitric Oxide 19, 199-204. 

Williams, J.L., Borgo, S., Hasan, I., Castillo, E., Traganos, F., and Rigas, B. (2001). Nitric oxide-releasing nonsteroidal anti-inflammatory drugs (Nsaids) alter the kinetics of human colon cancer cell lines more effectively than traditional Nsaids Implications for colon cancer chemoprevention. Cancer Res. 67, 3285-3289. 

Dunlap, T. (2008). Nitrates and NO-NSAIDs in cancer chemoprevention and therapy in vitro evidence querying the NO donor functionality. Nitric Oxide 79,115-124. 

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