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The existing nonsteroidal anti-inflammatory drugs differ in their relative specificities for COX-2 and COX-1; while aspirin and ibuprofen inhibit COX-2 and COX-1 enzymes, other NSAIDs appear to have partial COX-2 specificity, particularly meloxicam . [39] Aspirin is ≈170-fold more potent in inhibiting COX-1 than COX-2. [40]
The impetus for development of selective COX-2 inhibitors was the adverse gastrointestinal side-effects of NSAIDs.Soon after the discovery of the mechanism of action of NSAIDs, strong indications emerged for alternative forms of COX, but little supporting evidence was found.
Etodolac is 179 times more selective at blocking COX-2 than COX-1. [4] Unlike rofecoxib, both etodolac and celecoxib can fully inhibit COX-1 and are designated as having "preferential selectivity" toward COX-2. The R-enantiomer of etodolac is inactive against COX enzymes, but inhibits beta-catenin levels in hepatoma cells. [5]
COX-2 is an enzyme facultatively expressed in inflammation, and it is inhibition of COX-2 that produces the desirable effects of NSAIDs. [125] When nonselective COX-1/COX-2 inhibitors (such as aspirin, ibuprofen, and naproxen) lower stomach prostaglandin levels, ulcers of the stomach or duodenum and internal bleeding can result. [126]
COX is a common target for anti-inflammatory drugs. The most significant difference between the isoenzymes, which allows for selective inhibition, is the substitution of isoleucine at position 523 in COX-1 with valine in COX-2. The smaller Val 523 residue in COX-2 allows access to a hydrophobic side-pocket in the enzyme (which Ile 523 ...
Structure of COX-2 inactivated by Aspirin. In the active site of each of the two enzymes, Serine 516 has been acetylated. Also visible is the salicylic acid which has transferred the acetyl group, and the heme cofactor. There are at least two different cyclooxygenase isozymes: COX-1 (PTGS1) and COX-2 (PTGS2).
COX-1 is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin. Thromboxane A2, the major product of COX-1 in platelets, induces platelet aggregation. [20] [21] The inhibition of COX-1 is sufficient to explain why low dose aspirin is effective at reducing cardiac events.
Ketorolac is a non-selective COX inhibitor. [26] It is considered a first-generation NSAID, [15]: 279 a group of drugs that non-selectively inhibit both COX-1 and COX-2 enzymes, which can lead to gastrointestinal side effects. [27]