COX

Nonsteroidal anti-inflammatory drugs (NSAIDs) are beneficial in the treatment and prevention of Alzheimer's disease (AD). NSAIDs act by inhibiting cyclooxygenase (COX), an enzyme that occurs in constitutive and inducible isoforms, known respectively as COX-1 and COX-2. Recognition that COX-2 plays a key role in inflammation led to the hypothesis that COX-2 might represent the primary target for NSAIDs in AD, consistent with inflammatory processes occurring in AD brain.

KB3022
101001-34-7
103-90-2
Acetaminophen
103-90-2
116686-15-8
FK 3311
116686-15-8
120210-48-2
Tenidap
120210-48-2
121502-05-4
PD 127443
121502-05-4
1226895-20-0
ATB 346
1226895-20-0
123653-11-2
NS 398
123653-11-2
B0084-056331
Iguratimod
123663-49-0
NCX 466
1262956-64-8
130717-51-0
130717-51-0
13710-19-5
Tolfenamic Acid
13710-19-5
B0084-058185
Salicin
138-52-3
141505-32-0
Ibuprofen lysinate
141505-32-0
15307-79-6
Diclofenac Sodium
15307-79-6
15307-86-5
Diclofenac
15307-86-5

Background


The two isoforms of the COX enzyme, COX-1 and COX-2, are coded by the COX-1 and COX-2 gene, respectively. These two isoenzymes share about 60% gene homology; however, substantial differences exist between the gene and promoter structures of COX-1 and COX-2. The two isoforms of the COX enzyme, COX-1 and COX-2, are coded by the COX-1 and COX-2 gene, respectively. These two isoenzymes share about 60% gene homology; however, substantial differences exist between the gene and promoter structures of COX-1 and COX-2.

Historically, anti-inflammatory drugs originate from the discovery of plant extracts that were applied for the relief of pain, fever and inflammation. When salicylates were discovered to be the active components of Willow Bark, this enabled these compounds to be synthesized and acetyl-salicylic acid or Aspirin was developed. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat inflammation and pain. The cardinal signs of inflammation; including edema, hyperalgesia, and erythema, develop as an acute response to a local inflammatory insult. These symptoms result from the action of inflammatory agents such as bradykinin, histamine, neurokinins, complement, and nitric oxide, which can originate locally or from cells that infiltrate the site of insult. Elevated levels of prostaglandins (PGs) are also produced during inflammation and enhance or prolong signals produced by pro-inflammatory agents, but alone do not cause inflammation. NSAIDs reduce or prevent the production of PGs by direct inhibition of the cyclooxygenase (COX) enzymes. The observation that NSAIDs inhibit COX activity attests to the contribution of PGs to inflammation.

COX-1 is thought to produce PGs important for homeostasis and certain physiological functions and is expressed constitutively in most tissues and cells, although it can be induced in some cell lines under certain conditions. A second, inducible, form of COX was hypothesized to exist on the basis of the finding of a glucocorticoid-regulated increase in COX activity observed in vitro and in vivo in response to inflammatory stimuli. The isolation of a distinct gene and enzyme for COX-2 confirmed this hypothesis and led to the supposition that selective inhibition of inducible COX-2 would be anti-inflammatory, while preserving the physiological functions of COX-1 derived PGs. This hypothesis was corroborated by the discovery and synthesis of anti-inflammatory compounds that selectively and potently inhibit COX-2 but not COX-1. In contrast, NSAIDs inhibit both forms of COX at approximately equivalent concentrations. Selective inhibition of COX-2 only partially reduces the level of PGs at sites of either acute or chronic inflammation, in comparison to NSAIDs, which reduce PGs to undetectable levels. Therefore, COX-1 may contribute significantly to the total pool of PG at a site of inflammation. To date, the contribution of COX-1 to inflammation has not been clearly established. The substantial GI risk associated with the use of traditional nonselective NSAID therapy, coupled with the understanding that COX-2 is associated with the development of prostaglandins that produce pain and inflammation, led researchers to develop new agents with greater COX-2 selectivity.

A selective COX-2 inhibitor would have a similar ability to reduce pain and inflammation as a traditional NSAID but would not have any adverse effects on GI mucosa that can be linked to the inhibition of COX-1 activity. These agents also must not inhibit platelet function. The search for COX-2-specific durgs resulted in promising candidates such as valdecoxib, celecoxib, and rofecoxib. 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. Celecoxib is approximately 30 times more potent at inhibiting COX-2 than COX-1.

Reference:Timothy D. Brunson . EFFECT OF CYCLOOXYGENASE INHIBITORS ON RAT ROOT RESORPTION AND TOOTH MOVEMENT