NONO-NSAIDs

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most useful clinical therapies for the treatment of pain, fever and inflammation. However, the major mechanism by which NSAIDs exert their anti-inflammatory activity, inhibition of cyclooxygenase-derived prostaglandin synthesis, is also responsible for the gastrointestinal, renal and hepatic side effects observed mainly in patients undergoing long-term treatment of chronic conditions.

The most common side effects associated with NSAID administration are gastroduodenal erosions and ulcerations affecting around 15% of chronic NSAID users. While many of these clinical manifestations of NSAID-induced toxicity are mild, they may potentially develop into serious events such as bleeding, perforation, obstruction, and sudden death. Therefore, it is necessary to consider NSAID-induced toxicity as a serious public health problem contributing significantly to the morbidity and mortality of patients receiving these drugs. Furthermore, the gastric irritant effect of aspirin (1) can be a deterrent to its long-term use for the prophylactic prevention of adverse cardiovascular events such as stroke and myocardial infarction, or as a safe chemopreventive agent to avoid the recurrence of colorectal cancer (CRC).

Two different strategies have emerged to improve the safety profile of NSAIDs:
(a) The development of selective cyclooxygenase-2 (COX-2) inhibitors; and
(b) The linkage of a nitric oxide (•NO)-releasing moiety to classical NSAIDs (NO-NSAIDs).

The role of selective COX-2 inhibitors with respect to the adverse cardiovascular effects reported in some patients undergoing chronic treatment of pain and inflammation has attracted considerable recent attention. In this regard, the adverse hypertensive effect induced by rofecoxib (2) was the primary factor that prompted its withdrawal from the market.

In animal studies, nitrate-based NO-NSAIDs including the NO-aspirin (3), NO-naproxen (4), NO-flurbiprofen (5), and NO-diclofenac (6), have been shown to spare the gastrointestinal tract, even though they suppressed prostaglandin synthesis as effectively as the parent drugs. However, an important drawback to this design is the fact that production of •NO from nitrate esters requires a three-electron reduction, and this metabolic activation can decrease in efficiency on continued use of the drugs contributing to "nitrate tolerance".

O²-Unsubstituted N-diazen-1-ium-1,2-diolates (NONOates) have the potential to release •NO without metabolic activation (first-order kinetics). They possess structural diversity, dependable rates of •NO-release, and rich derivatization chemistry that facilitates targeting of •NO to specific organ and/or tissue sites. These features distinguish NONOates from currently available nitrate-based clinical vasodilators that require redox activation before •NO is released. We recently reported the synthesis, •NO-release profile, and biological evaluation of a novel group of nitric oxide-releasing non-steroidal anti-inflammatory prodrugs possessing a NONOate moiety attached to the carboxylic acid group of the traditional NSAIDs aspirin, ibuprofen, and indomethacin, the first in a series of NONO-NSAIDs.  These prodrugs showed equipotent anti-inflammatory properties compared to their NSAID counterparts in a carrageenan-induced rat paw edema assay in vivo, without significant gastric toxicity when administered orally. As part of our ongoing research program targeted toward the development of improved anti-inflammatory agents with a greater safety profile, we are working on the synthesis, in vitro COX-1/COX-2 inhibitory activity, in vivo anti-inflammatory activity, nitric oxide release data, and ulcerogenicity studies for a group of ester prodrugs of classical NSAIDs including (but not limited to) aspirin, ibuprofen and indomethacin.

Velazquez, C. A.; Praveen Rao, P. N.; Citro, M. L.; Keefer, L. K.; Knaus, E. E. O2-acetoxymethyl-protected diazeniumdiolate-based NSAIDs (NONO-NSAIDs): synthesis, nitric oxide release, and biological evaluation studies. Bioorg Med Chem 2007, 15, 4767-4774.

Velazquez, C.; Praveen Rao, P. N.; Knaus, E. E. Novel non-steroidal anti-inflammatory drugs possessing a nitric oxide donor diazen-1-ium-1,2-diolate moiety: design, synthesis, biological evaluation, and nitric oxide release studies. Journal of Medicinal Chemistry 2005, 48, 4061-4067.