Binding Of Celecoxib To Cox2 Isozyme

The hypothetical binding model for binding of celecoxib, the only selective "coxibs" type COX-2 inhibitor shown on Figure 24.15B, is purely speculative, based only on the crystallographic binding data reported for SC-558 (the p-bromophenyl analog of celecoxib) with the murine COX-2 isozyme.146 However, the celecoxib selectivity toward the COX-2 isozyme is most likely a result of the extension of the sulfonamide moiety into the extra hydrophilic-binding pocket, surrounded by His-90 (His-76 in hCOX-2) and Arg-513 (Arg-499 in hCOX-2). The opening of this additional pocket for binding is the result of the replacement of Ile-523

in the COX-1 with a smaller valine residue (Val 509 in hCOX-2). It should be pointed out that a similar hydrophilic pocket does exist in the COX-1 isozyme, but it is inaccessible because of the bulkier Ile-523 residue that guards the entrance to this side pocket of the COX-1 isozyme (see Fig. 24.15-A).

The COX-2/COX-1 selectivity ratios, estimated by different research groups, can be quite different (e.g., the reported selectivity ratio for celecoxib ranges any where from 0.003-0.7; for piroxicam, the range is 3.3-600). Thus, the selectivity ratios included in Table 24.1, obtained from one such study, is only valid for comparing their differences among these NSAIDs. Furthermore, recent reviews comparing the SAR among different structural classes of COX-2 inhibitors have indicated that there is little or no common pharmacophore required for their COX-2 selectivity, but minor changes within the structure type, in terms of molecular shape, lipophilicity, electronic density, flexibility, polarity, and hydrogen-bonding properties, can all have drastic effects in its COX selectivity.152,153

PIROXICAM AND MELOXICAM: THE DIFFERENCE IN THEIR COX SELECTIVITY

Piroxicam and meloxicam have nearly identical structural features but also have at least a ninefold difference in selectivity for meloxicam to COX-2 isozyme and an even larger difference in their relative risks for GI complications (i.e., piroxicam has the highest risk among NSAIDs, whereas meloxicam has very little or no such side effects) (Table 24.1). A closer comparison of their structure (Fig. 24.16), however, reveals no apparent reason for these differences, either in size, lipophilicity, or electronic properties, between the 2-pyridyl group (in piroxicam) and the 5-methyl-2-thiazoyl group (meloxicam) that may alter their ability to bind COX isozymes. It is unlikely that these drastic differences in their COX selectivity, especially the drug-induced GI toxicity, could be due solely to the binding of the parent molecules with such minor changes in their structures. Thus, could the observed differences, especially the differences in drug-induced GI side effects, be attributed to the involvement of an active metabolite of piroxicam and/or meloxicam?

The metabolism of piroxicam to its major active metabolite, 5'-hydroxypiroxicam and meloxicam to its

Tyr-385

A11-double bond binding region

Leu-384

— ) A14-double bond binding region

Ser-530

A8-double bond binding region

Arg-120

Tyr-385

Leu-384

Ser-530

A11-double bond binding region

A8-double bond binding region

Arg-120

5-double bond binding region

Tyr-355

OCH3 Ser-355

5-double bond binding region

Tyr-355

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