COX-2-selective nonsteroidal

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. 

Fowles RE. Potential cardiovascular effects of COX-2 selective nonsteroidal antiinflammatory drags. J Pain Palliat Care Pharmacother. 2003 17 27-50. 

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

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. 

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. 

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]. 

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). 

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. 

Kalgutkar, A. S., Crews, B. C., Rowlinson, S. W., Marnett, A. B., Kozak, K. R., Remmel, R. P., Marnett, L. J. Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors, Proc. Natl. Acad. Sci. USA 2000, 97, 925-930. 

Pfizer alleged that the claimed invention was invalid for, among other things, failure to comply with the written description requirement. The District Court found for Pfizer, holding that Rochester s claimed invention was invalid for failure to comply with the written description because the Rochester patent neither disclosed a nonsteroidal compound that selectively inhibits the COX-2 enzyme nor provided any idea how such a compound could be made other than by trial and error research.23 Instead of a specific description of the invention all the public received was a method of identifying and using compounds without any description of the compounds themselves. As the District Court explained in its decision,... 

Another example of fully automated PASP synthesis is the preparation of a 192-member 2D array of 1,5-biaryl pyrazoles. " The 1,5-biaryl pyrazole moiety is found in a number of important pharmaceuticals, such as the selective COX-2 inhibitor Celecoxib and the nonsteroidal antiinflammatory agent Tepoxaline. The synthetic route to the 1,5-biaryl pyrazoles, exemplified by the library member 42... 

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. 

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