Development of Selective COX-2 Inhibitors

Celecoxib was the first modern COX-2 inhibitor, which was introduced to the market in 1998. Developed by Monsanto/Searle, this drug is 375 times more selective for COX-2 over COX-1, based on assays with recombinant human enzymes (Fig. 5.88). [187] 

The second drug, which was marketed almost at the same time by Merck, was rofecoxib (Viox ). Within a few years, Vioxx became the company s product with the highest sales revenue, amounting to 2.6 billion US dollars. However, Merck had to with draw the drug from the market unexpectedly in 2004, because of serious side-effects, like increased risk of heart attacks, unstable Angina pectoris and strokes. 

A similar fate befell a series of other coxibs as well These, like Valdecoxib (Bextra ) had to be withdrawn from the market by Pfizer, or, like parecoxib (Pfizer) or etoricoxib (Merck), did not obtain regulatory approval in major markets at all (Fig. 5.89). 

The selectivity of drugs is generally assessed with the aid of in vitro or ex-vivo assay systems, and also in human whole blood as appropriate. Occasionally, however, the data show considerable variability. This appears to apply in particular to meloxicam, where, depending on the experimental set-up, almost any selectivity factor may be obtained. [188] COX- inhibitors show in general affinity to both isozymes, cyclooxygenase-1 and -2. In many cases the selectivity factor ranges from 1 to 100 (Fig. 5.90). [189] 

11 Syntheses of Modern Non-steroidal Anti-inflammatory Drugs 

---

NSAIDs block the activity of both isoforms. These findings have provided the impetns for the development of selective COX-2 inhibitors, which are proposed to act as potent anti-inflammatory agents by inhibiting COX-2 activity, withont the gastrointestinal and anti-platelet side effects commonly associated with NS AID use. These NS AID adverse effects are thought to be a result of COX-1 inhibition. Examples of these newer selective COX-2 inhibitors are celecoxib (Celebrex) and rofecoxib (Vioxx). 

Whereas the development of selective COX-2 inhibitors proved problematic, modern biological drugs" spur new hope for the effective treatment of rheumatoid diseases. 

The future development and clinical testing of selective COX-2 inhibitors will undoubtedly have far... 

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... 

The NSAIDs (eg, indomethacin, ibuprofen see Chapter 36) block both prostaglandin and thromboxane formation by reversibly inhibiting COX activity. The traditional NSAIDs are not selective for COX-1 or COX-2. Selective COX-2 inhibitors, which were developed more recently, vary—as do the older drugs—in their degree of selectivity. Indeed, there is considerable variability between (and within) individuals in the selectivity attained by the same dose of the same NSAID. Aspirin is an irreversible COX inhibitor. In platelets, which are anuclear, COX-1 (the only isoform expressed in mature platelets) cannot be restored via protein biosynthesis, resulting in extended inhibition ofTXA2 biosynthesis. 

The discovery of two cyclooxygenase isoforms (COX-1 and COX-2) led to the concept that the constitutive COX-1 isoform tends to be homeostatic in function, while COX-2 is induced during inflammation and tends to facilitate the inflammatory response. On this basis, highly selective COX-2 inhibitors have been developed and marketed on the assumption that such selective inhibitors would be safer than nonselective COX-1 inhibitors but without loss of efficacy. 

Aspirin is the only known NSAID that covalently bonds to serine and inhibits COX-1 more significantly than COX-2. Many systematic structural modifications have been carried out resulting in the development of APHS characterized by a 60-fold increase in activity and a 100-fold increase in selectivity for COX-2 than aspirin. Inhibition of COX-2 also occurs by acetylation of the same serine residue that is acetylated by aspirin, indicating that the mechanism of APHS inhibition is not identical to that of other selective COX-2 inhibitors (Kalgutkar et al., 1998a 1998b). 

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 interaction between potassium-sparing diuretics and NSAIDs is well documented (SED-14, 674). The major complications are deterioration of renal function and hjrper-kalemia. The risk associated with the non-selective COX-2 inhibitors is unknown. However, three patients had hyperkalemia (8.5, 5.4, and 5.1 mmol/1) after developing acute renal insufficiency while taking these drugs (8). 

Flosulide was shovm also to be a selective COX-2 inhibitor, less potent than NS 398 but with better pharmacokinetic properties (383). Flosulide was used as a lead for development of L-745,337 (85), which is the direct thio-... 

The recent developments of COX-2 specific NSAIDs has remarkably reduced and almost eliminated the plethora of side effects intimately associated with the traditional NSAIDs. In fact, several natural products have been duly isolated, purified, and identified as precisely selective COX-2 inhibitors. Now, with the availability of COX-2 based NSAIDs in the market, it has become rather important to strike a bonafide comparison of CADD methods for determining the relative binding affinities of COX-2 inhibitors. 

---