Cyclooxygenase Inhibitors - Part 4: Cyclooxygenase-2-Selective Inhibitors: Translating Pharmacology into Clinical Utility

Pharmacologic inhibition of COX enzymes

Insight into cyclooxygenase structure and function has helped clarify the mechanisms through which NSAIDs produce their therapeutic benefits and toxicity. The different ways in which nonselective NSAIDs and coxibs, the selective COX-2 inhibitors, interact with each isoenzyme can explain many of the observed clinical effects, both good and bad, of these agents. Furthermore, this understanding has also provided the basis for a rational approach to designing safer drugs.

The "classical" nonselective NSAIDs bind to both COX-1 and COX-2, interacting with the hydrophobic channel of the COX isoenzymes. Aspirin, unlike other NSAIDs, irreversibly acetylates a serine residue in both COX-1 and COX-2 to prevent binding of arachidonic acid. Other nonselective NSAIDs compete directly for arachidonic acid, inhibiting cyclooxygenase activity in a rapid but reversible manner.(23) Although nonselective NSAIDs bind both COX-1 and COX-2, each isoform is inhibited to different degrees. Coxibs, the COX-2-selective inhibitors, preferentially bind to and inhibit COX-2. Coxibs are selective agents because they bind COX-1 poorly and in a rapidly reversible manner, whereas they bind COX-2 more tightly. This occurs in 2 stages; binding of coxibs to COX-2 during the second stage is tight, with dissociation occurring only slowly (minutes to hours). Preferential inhibition of COX-2 is thought to be due to the additional space in the COX-2 hydrophobic channel, as well as to the presence of a side pocket in the channel. This side pocket can discriminate the coxibs from nonselective agents based on the different overall structures of these agents, in particular, by the presence in coxibs of specific side chains (Figure 2).(21)

Figure 2.
Structure of the COX-1 and COX-2 enzymes. (21)
Schematic showing active site similarities and differences. ILE = isoleucine; VAL - valine.

Cronstein BN. Cyclooxygenase-2-selective inhibitors: translating pharmacology into clinical utility. Cleve Clin J Med 2002;69:SI13-19.

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