COX-2 Inhibitors - Research History

Research History

For more details on this topic, see Discovery and development of cyclooxygenase 2 inhibitors.

The COX-2 enzyme was discovered in 1988 by Daniel Simmons, a Brigham Young University researcher. The mouse COX-2 gene was cloned by UCLA scientist Dr. Harvey Herschman, a finding published in 1991.

The basic research leading to the discovery of COX-2 inhibitors has been the subject of at least two lawsuits. Brigham Young University has sued Pfizer, alleging breach of contract from relations BYU had with the company at the time of Dr. Simmons work. A settlement was reached in April 2012 in which Pfizer agreed to pay $450 million. The other litigation is based on United States Pat. No. 6,048,850 owned by University of Rochester, which claimed a method to treat pain without causing gastro-intestinal distress by selectively inhibiting COX-2. When the patent issued, the university sued Searle (later Pfizer) in a case called, University of Rochester v. G.D. Searle & Co., 358 F.3d 916 (Fed. Cir. 2004). The court ruled in favor of Searle in 2004, holding in essence that the university had claimed a method requiring, yet provided no written description of, a compound that could inhibit COX-2 and therefore the patent was invalid.

In the course of the search for a specific inhibitor of the negative effects of prostaglandins which spared the positive effects, it was discovered that prostaglandins could indeed be separated into two general classes which could loosely be regarded as "good prostaglandins" and "bad prostaglandins", according to the structure of a particular enzyme involved in their biosynthesis, cyclooxygenase.

Prostaglandins whose synthesis involves the cyclooxygenase-I enzyme, or COX-1, are responsible for maintenance and protection of the gastrointestinal tract, while prostaglandins whose synthesis involves the cyclooxygenase-II enzyme, or COX-2, are responsible for inflammation and pain.

The existing non-steroidal anti-inflammatory drugs (NSAIDs) differ in their relative specificities for COX-2 and COX-1; while aspirin and ibuprofen are equipotent at inhibiting COX-2 and COX-1 enzymes, other NSAIDs appear to have partial COX-2 specificity, particularly meloxicam (Mobic). Studies of meloxicam 7.5 mg per day for 23 days find a level of gastric injury similar to that of a placebo, and for meloxicam 15 mg per day a level of injury lower than that of other NSAIDs; however, in clinical practice meloxicam can still cause some ulcer complications.

Many COX-2-specific inhibitors have been removed from the U.S. market. As of December 2011, only Celebrex (generic name is celecoxib) is still available for purchase.

Valdecoxib and rofecoxib are about 300 times more potent at inhibiting COX-2, than COX-1, suggesting the possibility of relief from pain and inflammation, without gastrointestinal irritation, and promising to be a boon for those who had experienced such adverse effects previously or had comorbidities that could lead to such complications. Celecoxib is approximately 30 times more potent at inhibiting COX-2 than COX-1, with etoricoxib being 106 times more potent. Also, Tribulus terrestris was shown to have strong inhibitory activity on COX-2.