COX-2-selective nonsteroidal anti-inflammatory drugs

Elder DJE, HaltonDE, Hague A, etal. Induction of apoptotic cell death in human colorectal carcinoma cell lines by a cyclooxygenase-2 (COX-2)-selective nonsteroidal anti-inflammatory drug independence from COX-2 protein expression. Clin Cancer Res 1997 3 1679-1683. 

Jackson LM, Hawkey CJ. Cox-2 selective nonsteroidal anti-inflammatory drugs. Drugs 2000 59 1207-16. 

Celebrex (celecoxib) is a selective cyclooxygenase (COX)-2 inhibitor nonsteroidal anti-inflammatory drug chemically designated as 4- [5-(4-methylphenyl)-3- (trifluoromethyl) -1 -H-pyrazol-1 -yl)benzenesulfon-amide. It is a diaryl-substituted pyrazole with an empirical formula of Cj Hj FjNjO S and a molecular weight of 381.38. The potent anti-inflammatory effects of an original diarylheterocyclic compound, phenylbutazone, directed scientists to pharmacologically manipulate this chemical scaffold. As a result, celecoxib was the first of the coxibs to be introduced in 1999 by Searle/Pharmacia (now part of Pfizer Inc., USA) [1]. 

TABLE 33—3. Selected Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and Cyclooxygenase-2 (COX-2) Inhibitors... 

There is intriguing evidence that shows that nonsteroidal anti-inflammatory drugs have anticancer activity that could potentially lead to the use of these drugs or the newer generation of selective cox-2 inhibitors for their anticancer activity. Chapter 22 by Pyo et al. will expand upon this and address the impact of the interesting observation that a combination of the selective cox-2 inhibitor, SC-236, and radiation was found to cause a dose enhancement factor of at least 1.4 at a surviving fraction of 0.1 (71). 

COX-1 and COX-2 are the targets of the nonsteroidal anti-inflammatory drugs (NSAID, see Chapter 28). Indirectely the effect of these enzymes is also inhibited by corticosteroids (see also Chapter 26) through a decrease of the availibility of its substrate arachidonic acid by inhibition of phospholipase A2. Relatively new drugs, known as COX-2 selective inhibitors or coxibs (celecoxib, rofecoxib and others), are used as specific inhibitors of COX-2. 

Many nonsteroidal anti-inflammatory drugs of different chemical structures (Fig. 5) have been introduced for the treatment of inflammatory and painful conditions. Many years of clinical experience with these drugs have shown that there is no induction of tolerance or dependence and no respiratory depression as seen with opioids. The major side-effects of these compounds with COX-1 selectivity or balanced COX-1 and COX-2 inhibition are damage to the gastric mucosa, prolongation of bleeding time and renal failure. 

Nonsteroidal anti-inflammatory drugs (NSAlDs) nonselectively inhibit the activities of both COX-1 and COX-2. Out of concern for the gastrointestinal side effects of NSAID, scientists have discovered and developed many specific COX-2 inhibitors that facilitate a safer choice for controlling inflammatory diseases (73). Eor example, NS-398, a selective COX-2 inhibitor, has been shown to reduce tension (mechanical stress)-induced PGE2 production from periodontal ligament cell cultures (74). 

The eight groups of nonsteroidal anti-inflammatory drugs are salicylates, parachlorobenzoic acid derivatives, pyrazolone derivatives, propionic acid derivatives, fenamates, oxicams, phenylacetic acid, and selective COX-2 inhibitors. 

Nonsteroidal anti-inflammatory drugs (NSAIDs) Standard dosage regimens of aspirin or traditional NSAIDs (e.g., ibuprofen) selective cyclooxygenase-2 (COX-2) inhibitors should be used in patients at risk for upper Gl bleeding use with caution in renal insufficiency... 

Celecoxib 24, a highly selective COX-2 inhibitor and a nonsteroidal anti-inflammatory drug (NS AID), is used for the treatment of arthritis and pain. The core skeleton of Celecoxib 24 is a 3-trifluoromethylpyrazole ring, which has been synthesized by [2 - - 3] cyclization and condensation of 1,3-diketones or their equivalents. Figure 12.3 summarizes three synthetic approaches toward 3-trifluoromethylpyrazole compounds via condensation of 1,3-diketones or a,[3-unsaturated ketones with arylhydrazine (route A, Schemes 12.1-12.3), via [2 - - 3] cycloaddition of trifluor-oacetamide with substituted ethenes or acetylene (route B, Schemes 12.4 and 12.5), and via cycloaddition of CFa-alkene with C-N=N unit (route C, Scheme 12.6). 

Inhibition of COX that leads to less proinflammatory PG production at the injury site is the major mechanism of action of nonsteroidal anti-inflammatory drugs (NSAID) (4). Molecular cloning studies have identified two forms of COX (5,6), COX-1, a constitutive form responsible for housekeeping functions, and COX-2, an inducible form that mediates many of the inflammatory and inducible effects. Both forms carry out essentially the same catalytic reaction and have similar primary sequences (5,6). Selective inhibitors of the inducible COX-2 would therefore be ideal as NSAID that are free of side effects (7). 

Celecoxib (Celebrex) is a selective cyclooxygenase-2 (COX-2) inhibitor prescribed as a nonsteroidal anti-inflammatory drug (NSAID). The Paal-Knorr cyclization was the crucial step in preparing tri-substituted keto-pyrroles as COX-2 inhibitors. Here, the tri-ketone substrates were prepared in situ from phenacyl bromide and 1,3-diketone. ... 

Symbioimine (35) also significantly inhibited cyclooxygenase-2 (COX-2) activity (32%) at 10 pM. Meanwhile, it had only weak inhibitory ability (5%) toward COX-1 at 10 pM [72]. The overexpression of COX-2 has been observed in many kinds of tumors, and its role in carcinogenesis and angiogenesis has been extensively investigated [76,77]. Several COX-2-selective inhibitors, such as rofecoxib, celecoxib, and sulindac, have been developed. Because of its moderate subtype specificity, symbioimine (35) may be useful for the development of new nonsteroid anti-inflammatory drugs (NSAID) to treat COX-associated diseases, such as inflammatory diseases and cancer. 

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