Design, Synthesis And Biological Evaluation Of NO Donor Selective COX-2 Inhibitor

Selective COX-2 inhibitors have been widely used in the treatment of acute and chronic inflammation states because of their good anti-inflammatory activities and low gastrointestinal side effects. Yet, these drugs are not without limitations. In recent years, many side effects occurred at high doses and/or with long-term use, including ulcer exacerbation in high-risk patients, delayed gastrointestinal ulcer healing, kidney toxicity, especially cardiovascular effects.As a chemical messenger inside and between cells, nitric oxide (NO) regulates a wide range of important cellular functions, including the central nervous, cardiovascular and immune systems. NO plays an important cytoprotective role in GI homeostasis by helping maintain mucosal blood flow, by optimizing mucus secretion, and by inhibiting platelet and inflammatory-cell activation. The NO-NSAIDs are a recently described class of NSAIDs derivatives generated by chemically coupling a NO-releasing moiety to the parent NSAIDs via a short-chain linkage. The rationale behind this coupling is that NO released from these derivatives would enhance GI mucosal defenses and prevent the pathogenic events that occur with suppression of PG synthesis, such as reduced gastric mucosal blood flow, increased TNFαplasma levels and leucocyte- endothelial cell adherence. Thus, NO released by these compounds may counteract the detrimental effect of NSAIDs on COX inhibition.Structure activity relationship (SAR) studies have been shown that tricycle compound was a kind of COX-2 inhibitors with good selective properties. Pyrazole compounds with 1, 5-diaryl substitution and a small aliphatic moiety at position 3 have been identified as potent selective COX-2 inhibitors with good pharmacokinetic profiles. The intrinsic tissue-protective and anti-inflammatory properties of NO may help reduce the side effects still associated with COX-2 selective inhibitors. We report herein the synthesis and COX-2 inhibition of a series of novel 1, 5-diaryl pyrazole derivatives containing a NO-donor group (Nitrate or Furoxan) at position 3 which have a great potential as COX-2 selective inhibitors with low side effects.