Rofecoxib, structure

Again, detailed structural information at a molecular level was the key. Once these pictures were available slight chemical differences between the COX-1 and COX-2 isoenzymes could be seen COX-2 had a side pocket while COX-1 didn t. This meant that a molecule that could dock into the COX-2 side pocket (binding site) but not into COX-1 would specifically block COX-2 without touching COX-1. In 1999 this hope was realized with the availability of COX-2 selective anti-inflammatories such as Rofecoxib and Celecoxib that can be as much as 50-fold selective for the target. 

Figure 13.8 Comparison of the enrichment obtained with the combined pharmacophore model (PPP model) resulting from a 1,5-A PPP cluster radius with the results of retrospective screening using the COX-2 inhibitors Rofecoxib, M5, and SC-558 as seed structures (courtesy S. Renner).

A close structural analog of the non-selective COX inhibitor diclofenac, lumiracoxib displays a 500-fold greater selectivity for COX-2 than COX-1 in vivo and exhibits a unique pharmacologic profile that includes rapid absorbance and a relatively short plasma half-life (41, 42). Lumiracoxib lacks the tricyclic structure of the diarylheterocycle class of COX-2 selective inhibitors (e.g., celecoxib and rofecoxib) and does not contain a sulfonamide or sulfone group. Although structurally related, lumiracoxib and diclofenac exhibit large differences in the selectivity of COX-2 inhibition, and the molecular basis for this... 

A sulfur component is necessary for the receptor binding of both celecoxib and rofecoxib, but their structures differ and they have different potentials for causing allergic reactions. Consequently, celecoxib is thought to be contraindicated in patients with a history of allergy to sulfonamides. The available data on the immunological tolerability profile of celecoxib and rofecoxib are scanty but merit attention. 

A related phenomenon is the similar requirement of a 1,3 relationship of the 4-sulfo-nylphenyl ring and a structural feature of the scaffold. In the rofecoxib series, the relative position of carbonyl of the furanone is critical. 

Broader variations on the scaffold model have been reported in the patent literature. A prodrug of the rofecoxib furanone template has been reported (366). The cis-stilbene-like structure (68) can undergo metabolic oxidation to produce the selective 2,3-diary furanone. A variation on the 1,2 vicinal substitution is the reported analog (69), with geminal positioning of the two aryl rings off the exocy-clic olefin of the butyrolactone template (367, 368). 

Structures of cyclooxygenase-2 (COX2) selective inhibitors. (A) Celecoxib and (B) Rofecoxib. 

Shih Chen et al. (Columbus, USA) modified the structure of rofecoxib to create compouuds that mimicked the surface electrostatic poteutial of celecoxib, oue of which showed a substantial increase in apoptotic activity." What a challenge for the future ... 

To simplify things, consider a meta-analysis of a series of trials that are of two sorts, those comparing rofecoxib with naproxen and those comparing rofecoxib with placebo. These have the structure of an incomplete blocks design. If a model is fitted with trial as a factor and treatments as another factor at three levels - rofecoxib, naproxen, placebo -it is actually the rofecoxib results that permit the comparison of naproxen and placebo. To try to use this comparison to justify pooling placebo and naproxen is a hopelessly circular argument. To the extent that the model above is used, all that will happen is that rofecoxib will be separately compared with placebo using those trials in which they appeared. 

COX-2 Inhibitors Induce Apoptosis with Considerable Differences in Potency. The apoptotic effects of a panel of COX-2-specific inhibitors on human prostate cancer cell lines were evaluated. Table 1 shows that the COX-2 inhibitors, NS398, DuP697, rofecoxib and celecoxib, are similar structurally and with respect to their potencies in COX-2 inhibition (79). In addition, as we reported previously for celecoxib (66), NS398, DuP697, and rofecoxib were capable of inducing apoptosis in both LNCaP and PC-3 cells, as indicated by the characteristic apoptotic features including DNA laddering and caspase-3 (EC 3.4.22.1) activation (Fig. IB and C only data for PC-3 cells is shown). Similarly,... 

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