COX-2 selective inhibitors

The different furanones 104 were tested for their potency as inhibitors of PGE2 production both in transfected Chinese hamster ovarian (CHO) cells expressing human COX-2 and in human whole blood. Compound 104r proved to be an orally active and selective COX-2 inhibitor that is devoid of the ulcerogenic effect at >100 times the dose for antiinflammatory, analgesic, and antipyretic effects (99BMC3187). 

Since COX-2 is overexpressed in tumour cells, such as those of colorectal cancer, it was anticipated that selective COX-2 inhibitors may inhibit tumour growth. 

The first two selective COX-2 inhibitors to be marketed and subjected to in depth clinical trials were celecoxib and rofecoxib. Both compounds are as effective as standard NSAIDs in rheumatoid arthritis, osteoarthritis and for pain following orthopaedic or dental surgery. Gastrointestinal side effects were far fewer than with comparator diugs and in fact were no... 

COX-2 synthesises PGI2 (prostacyclin) and the high incidence of myocardial infarctions with selective COX-2 inhibitors has been attributed to inhibition of COX-2 in vascular tissues. Prostacyclin, made by blood vessel walls, inhibits aggregation of platelets and maintains a balance with thromboxane. Thromboxane, which is released by platelets, promotes clotting. Prostacyclin is synthesised mostly by COX-1, but in humans selective COX-2 inhibition reduces its biosynthesis in vivo. This reduced synthesis may lead to an overactive thromboxane system and increased risk of thromboembolism. 

The possibility still exists that selective COX-2 inhibitors may be used to treat cancer if the beneficial effect outweighs the side effects. They may also have a therapeutic role in treating premature labour, since labour is induced partly through the uterotonic effect of PGs synthesised by COX-2. Non-selective NSABDs such as indomethacin will also delay premature labour but they are contraindicated for this condition since they also cause early closure of the ductus arteriosus through inhibition of COX-1, which synthesises PGs maintaining patency of the ductus [5]. 

The precise side effect profile of the selective COX-2 inhibitors however, will only be known after several years of clinical use. 

Highly selective COX-2 inhibitors - coxibs (rofecoxib, celecoxib, or less popular - valdecoxib, etoricoxib parecoxiband lumiracoxib) - were found to be well tolerated in a series of placebo-controlled clinical trials [8]. However, rofecoxib and valdecoxib have been withdrawn from the market because of an increased incidence... 

With the availability of NSAIDs with COX-2 selectivity, clinicians postulated that these agents would avoid the need to add an additional prophylactic agent to therapy in patients with PUD risk factors. However, selective COX-2 inhibitors have not been shown to be any more effective than the combination of a PPI and a non-selective NSAID in reducing the incidence of ulcers, and questions remain regarding their long-term cardiovascular safety. 

Two large trials, the Vioxx Gastrointestinal Outcomes Research (VIGOR) study and the Celecoxib Long-term Arthritis Safety Study (CLASS), compared selective COX-2 inhibitors and traditional, non-selective NSAID therapy in terms of their ability to prevent clinical PUD (i.e., symptomatic ulcers and ulcer complications). VIGOR (9-month median follow-up) demonstrated that rofecoxib (50 mg daily) therapy was significantly more efficacious than naproxen.28 The CLASS study (6-month median follow-up) found that high-dose celecoxib (400 mg twice daily) was superior to non-selective NSAID therapy (either ibuprofen 800 mg three times daily or diclofenac 75 mg twice daily).29... 

Selective COX-2 inhibitors are not superior to PPIs in preventing NSAID-related PUD. One randomized, place-bo-controlled trial that included 267 patients at high risk for ulceration (arthritic patients with a previously healed bleeding ulcer) compared celecoxib 200 mg twice daily to the combination of diclofenac 75 mg twice daily plus omeprazole 20 mg daily.32 After 6 months, the risk for recurrent bleeding was found to be similar between groups (celecoxib, 4.9% and diclofenac/omeprazole, 6.4%) the authors concluded that neither of these therapies can completely prevent recurrent ulcer complications. 

Scheme 2.218. Examples of tricyclic compounds as selective COX-2 inhibitor.

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). 

Selective COX-2 inhibitors are currently being investigated in cancer patients in phase I and early phase II clinical trials. The currently available data would suggest that specific inhibitors of COX-2 have the potential to increase the therapeutic ratio of radiotherapy in tumors that express COX-2, and that clinical investigation of this interaction is warranted. 

Prostaglandins and Cyclooxygenase COX-2 Expression and Cancer Underlying Mechanisms of COX-2 Enzyme and Its Inhibitors on Cancers Effect of COX or Selective COX-2 Inhibitors on Cancer Prevention... 

Selective COX-2 inhibitors have also been shown to prevent early and late forms of colorectal neoplasia in rat models. Reddy et al. showed that administration of celecoxib inhibited aberrant colonic crypt foci (ACF) induction and multiplicity by about 40-49% in an azoxymethane-induced ACF rat model (81). Later the same investigators also showed that dietary administration of celecoxib can inhibit both the incidence and multiplicity of colon tumors by about 93 % and 97 %, respectively in the same rat model (82). Other researchers reported similar results with the Min mouse model (52). There is little data on human clinical trials with selective COX-2 inhibitors for colorectal tumor prevention. Recently Steinbach et al. conducted a double-blind, placebo-controlled study with 77 patients with FAP, and reported that treatment with celecoxib, a selective COX-2 inhibitor, for 6 mo led to a significant reduction (28%) in the number of colorectal polyps in these patients (50). Collectively, COX-2 nonspecific or specific NSAIDs appear to have chemopreventive activity against colorectal cancer development. Selective... 

Selective COX-2 inhibitors are ideal agents to combine with chemoradiotherapy for several reasons. First, they have been shown to enhance the effect of various chemotherapeutic agents and radiation on cancer cells. Second, selective COX-2 inhibitors are relatively safe. They do not have severe gastrointestinal toxicity, which is common in many nonselective NSAIDs. For example, celecoxib, a selective COX-2 inhibitor which is currently being used for patients with arthritis, is 375-fold more selective for COX-2 compared to COX-1 (94), and in large randomized, multicenter, placebo-controlled, double-blind trials conducted in patients with rheumatoid arthritis, celecoxib proved to be less toxic than nonselective inhibitors of COX-1 and COX-2, and no more toxic than a placebo (95). Third, high-dose celecoxib (600 mg bid) has no effect on serum thromboxane or platelet function (96). This is obviously important in patients receiving... 

Jtini P, Rutjes AWS, Dieppe PA. Are selective COX 2 inhibitors superior to traditional non steroidal antiinflammatory drugs Adequate analysis of the CLASS trial indicates that this may not be the case. BMJ 2002 324 1287-8. 

Wallace JL. Selective COX-2 inhibitors Is the water becoming muddy Trends Pharmacol Sci. 1999 20 4-6. 

Celecoxib (Celebrex) and rofecoxib (Vioxx) are highly selective COX-2 inhibitors. Because of this, they produce less erosion of the GI mucosa and cause less inhibition of platelet aggregation than do the nonselective COX inhibitors. Short-term (6 months-to a year) clinical trials have shown that celecoxib and rofecoxib produce less GI toxicity than nonselective NSAIDs. However, serious GI bleeding and ulceration have occurred in patients taking these drugs, and long-term prospective studies of their safety have yet to be completed. Like the nonselective NSAIDs, the selective COX-2 inhibitors can produce renal side effects such as hypertension and edema. 

Meloxicam (Mobic), recently introduced for the treatment of osteoarthritis, is also used for rheumatoid arthritis and certain acute conditions. Although meloxicam is sometimes reported to be a selective COX-2 inhibitor, it is considerably less selective than celecoxib or rofecoxib. Its adverse effects are similar to those of piroxicam and other NSAIDs however, the frequency of GI side effects is lower for meloxicam than for piroxicam and several other NSAIDs. 

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