Discovery of COX-3 enzyme may lead to novel drugs

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Discovery of COX-3 enzyme may lead to novel drugs

Provo, UT The discovery of COX-3, a new form of the cyclo-oxygenase enzyme,

has given rise to the hope that it could lead to the development of a novel

class of drugs, just as the identification of 2 forms of the enzyme COX-1

and COX-2 during the early 1990s led to the development of the coxibs. The

first generation of these agents, celecoxib (CELEBREX®, Pfizer) and

rofecoxib (Vioxx®, Merck), are currently among the best-selling drugs in the

world.

The new enzyme also appears to be the target on which acetaminophen acts to

exert its analgesic and antipyretic effects and so could explain at last

the mechanism of action of this commonly used agent.

The discovery of COX-3 was made by the same team that first differentiated

the COX-1 and COX-2 enzymes, led by Dr Dan (Brigham Young

University, Provo, Utah). They describe their findings in the Proceedings of

the National Academy of Science, in a paper published online the week of

September 16 [1].

Is this how acetaminophen exerts its effects?

The researchers describe COX-3 as a third distinct COX isoenzyme but note

that it is made from the COX-1 gene. They identified the new variant in

canine brains and then tested its reaction to various drugs in insect cells.

They also looked for COX-3 in human tissue samples and found it was

expressed at the highest levels in the heart and the brain.

COX-3 is significantly more sensitive to acetaminophen than either COX-1 or

COX-2, the group reports. They speculate that inhibition of COX-3 in the

brain and spinal cord may be the long-sought-after mechanism of action of

this drug and that this proposed mode of action also extends to pyrazolone

drugs such as dipyrone and the related compounds aminopyrine and antipyrine.

The new enzyme can also be inhibited by some nonsteroidal anti-inflammatory

drugs (NSAIDs), the researchers continue, but the different sensitivity of

the enzyme to the analgesic/antipyretic drugs such as acetaminophen and the

NSAIDs suggest that highly selective inhibitors can be made for COX-3.

" As we continue to examine this new enzyme, we are enlisting the aid of the

pharmaceutical industry to apply this discovery in a way that benefits

people suffering from pain and fever, " comments in a press release

issued by Brigham Young University.

Another discovery made at the same time was the finding of 2 smaller

COX-1-derived proteins (partial COX-1, or PCOX-1, proteins). These appear to

be related to the COX enzymes and are abundant in the canine brain, but

their function remains unclear. " I am excited by the potential of these new

PCOX proteins, " commented. " I want to know what they are doing and

if they play a role in diseases or disorders of the brain. "

Is there a COX continuum of enzymes and products?

" Simmon's group has provided another significant step forward. . . .  " in

the quest to understand the mechanism of action of the NSAID group of drugs,

say 2 researchers writing in a commentary that will appears alongside the

COX-3 paper in the Proceedings [2]. One of the authors is Dr Warner

from the Harvey Research Institute (Barts and the London School of

Medicine and Dentistry), which was founded by Sir Vane, winner of the

Nobel Prize for medicine in 1982 for the discovery that aspirin works by

inhibiting cyclo-oxygenase. In fact, Vane nominated the COX-3 paper for

publication in the journal.

The commentary suggests that the most significant implication of the new

study is the possibility that that there could be multiple COX isoenzymes

derived from just 2 distinct genes, providing a COX continuum of enzymes and

products. " Could the presence of multiple isoforms of COX-1 and COX-2

explain why there are so many different NSAIDs on the market and why

different patients appear to get benefit from different types of NSAID? If

we express variants of COX-1 and COX-2, could different drugs inhibit

different variants to different extents? Indeed, could these findings help

us to understand some of the side effects of NSAIDs and COX-2-selective

inhibitors? "