Cyclooxygenases are enzymes that take part in a complex biosynthetic cascade that results in the conversion of polyunsaturated fatty acids to prostaglandins and thromboxane(s).
[1] Their main role is to catalyze the transformation of arachidonic acid into the intermediate prostaglandin H2, which is the precursor of a variety of prostanoids with diverse and potent biological actions.
COX-1 is responsible for the synthesis of prostaglandin and thromboxane in many types of cells, including the gastro-intestinal tract and blood platelets.
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.
Before the confirmation of COX-2 existence, the Dupont company had developed a compound, DuP-697, that was potent in many anti-inflammatory assays but did not have the ulcerogenic effects of NSAIDs.
[7][8] Celecoxib and other COX-2 selective inhibitors, valdecoxib, parecoxib, and mavacoxib, were discovered by a team at the Searle division of Monsanto led by John Talley.
[9][10] Early studies showed that, when inflammation is induced, the affected organ unexpectedly develops an enormous capacity to generate prostaglandins.
In 1991, during the investigation of the expression of early-response genes in fibroblasts transformed with Rous sarcoma virus, a novel mRNA transcript that was similar, but not identical, to the seminal COX enzyme was identified.
Another group discovered a novel cDNA species encoding a protein with similar structure to COX-1 while studying phorbol-ester-induced genes in Swiss 3T3 cells.
Encouraged by the "concept testing" experiments with selective inhibitors, and armed with several solid leads and clear idea of the nature of the binding site, development of this field was rapid.
Efforts have been made to convert NSAIDs into selective COX-2 inhibitors such as indometacin by lengthening of the alkylcarboxylic acid side-chain, but none have been marketed.
Structure activity relationship (SAR) studies for diaryl heterocyclic compounds have indicated that a cis-stilbene moiety and changes in the para-position of one of the aryl rings play an important role in COX-2 selectivity.
It is known that a SO2NHCOCH3 moiety as in parecoxib, which is a prodrug for valdecoxib, is 105 – 106 more reactive acetylating agent of enzyme serine hydroxyl groups than simple amides.
For optimal activity and selectivity of the coxibs, a 4-methylsulfonylphenyl attached to an unsaturated (usually) five-membered ring with a vicinal lipophilic group is required (rofecoxib).
The SO2CH3 can be replaced by SO2NH2, wherein the lipophilic pocket is occupied by an optionally substituted phenyl ring or a bulky alkoxy substituent (celecoxib).
All of the coxibs achieve sufficient brain concentrations to have a central analgesic effect, and all reduce prostaglandin formation in inflamed joints.
[18] Parecoxib sodium is a water-soluble inactive ester amide prodrug of valdecoxib, a novel second-generation COX-2-specific inhibitor and the first such agent to be developed for injectable use.
[19] On the other hand, when Valdecoxib is taken orally it is absorbed rapidly (1–2 hours), but presence of food can delay peak serum concentration.
Patients with chronic kidney disease do not appear to have different plasma concentration curve (AUC) compared to healthy individuals.
It has though been reported that patients with moderate hepatic impairment have increased plasma concentration curve (AUC) by approximately 40%.
[17] A study showed that when a subject was given 400 mg dose, the amount of unchanged drug in the plasma 2.5 hours postdose suggest a modest first pass effect.
[24] The APPROVe (Adenomatous Poly Prevention on Vioxx) study was a multicentre, randomized, placebo-controlled, double blind trial aimed to assess the effect of three-year treatment with rofecoxib on recurrence of neoplastic polyps in individuals with a history of colorectal adenomas.
The trial was stopped early (2 months before expected completion) on recommendations of its data safety and monitoring board because of concerns about cardiovascular toxicity.
[25] When looking at the results of the study, it showed a statistically significant increase in cardiovascular risk when taking rofecoxib compared to placebo[25][26] beginning after 18 months of treatment.
Nussmeier et al. (2005) showed in a study increase in incidence of cardiovascular events when taking parecoxib and valdecoxib (compared to placebo) after coronary artery bypass surgery.
If this were the explanation for the increased cardiovascular risk then low-dose aspirin should negate this effect,[26][28] which was not the case in the APPROVe trial.
They showed that in spontaneously hypertensive rats (SHR) non-selective NSAIDs and the coxibs produce oxidative stress, indicated by enhanced vascular superoxide(O2−) content and elevated peroxide in plasma, which is in tune with enhanced expression of NADPH oxidase, which was noticed with use of diclofenac and naproxen and, to a lesser degree, rofecoxib and celecoxib.
[29] Among other hypotheses are increased blood pressure, decreased production of epi-lipoxins (which have anti-inflammatory effects), and inhibition of vascular remodeling when using selective COX-2 inhibitors.