Cyclooxygenase 2 inhibitors

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). Their main role is to catalyze the
transformation of arachidonic acid into the intermediate
prostaglandin H2, which is the procursor of a variety of
prostanoids with diverse and potent biological actions.
Cyclooxygenases have two main isoforms that are called
COX-1 and COX-2 (as well as a COX-3). COX-1 is
responsible for the synthesis of prostaglandin and
thromboxane in many types of cells, including the gastro-
intestinal tract and blood platelets. COX-2 plays a major
role in prostaglandin biosynthesis in inflammatory cells and
in the central nervous system. Prostaglandin synthesis in
these sites is a key factor in the development of inflammation
and hyperalgesia. COX-2 inhibitors have analgesic and anti-
inflammatory activity by blocking the transformation of
arachidonic acid into prostaglandin H2 selectively.

Structure Activity Relationship (SAR)

DuP-697 was a building block for
synthesis of COX-2 inhibitors and
served as the basic chemical model
for the coxibs that are the only
selective COX-2 inhibitors on the
market today. DuP-697 is a diaryl
heterocycle with cis-stilbene moiety.
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. Celecoxib and parecoxib have a sulfonamide
substituent (SO2NH2) in para-position on one of the aryl rings
while etoricoxib and rofecoxib have a methylsulphone
(SO2CH3). The oxidation state on the sulfur is important for
selectivity, sulfones and sulfonamides are selective for COX-
2 but sulfoxides and sulfides are not. The ring system that
is fused in this stilbene system has been extensively

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 manipulated to include every imaginable heterocyclic and
carbocyclic skeleton of varying ring sizes. 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. Due to
the fact that varying kinetic mechanisms affect potency for
COX-1 versus COX-2, relying Potency and selectivity in
human whole blood is used by many groups and has been
accepted as a standard assessment of COX-2 potency and
selectivity.

The relationship between amino acid profile of COX-2

enzyme and inhibition mechanism

One of the keys to developing COX-2 selective drugs is the larger

active site of COX-2 which makes it possible to make
molecules too large to fit into the COX-1 active site but still
able to fit the COX-2. The larger active site of COX-2 is partly
due to a polar hydrophilic side pocket that forms because of
substitution of Ile523, His513, and Ile434 in COX-1 by

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 Val523, Arg513, and Val434 in COX-2. Val523 is less bulky
than Ile523 which increases the volume of the active site.
Substitution of Ile434 for Val434 allows the side chain of
Phe518 to move back and make some extra space. This
side pocket allows for interactions with Arg513 which is a
replacement for His513 of COX-1. Arg513 is thought to be a
key residue for diaryl heterocycle inhibitors such as the
coxibs. The side chain of Leu384, at the top of the receptor
channel, is oriented into the active site of COX-1 but in COX-
2 it is oriented away from the active site and makes more
space in the apex of the binding site. The bulky sulfonamide
group in COX-2 inhibitors such as celecoxib and rofecoxib
prevent the molecule from entering the COX-1 channel. 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 SO 2NH2 where
the lipophilic pocket is occupied by an optionally substituted
phenyl ring or a bulky alkoxy substituent (celecoxib). Within
the hydrophilic side pocket of COX-2 the oxygen of the
sulfonamide (or sulfone) group interacts with Hist90, Arg513
and Gln192 and forms hydrogen bonds. The substituted
phenyl group at the top of the channel interacts with the
side chains of amino acid residues through hydrophobic and
electrostatic interactions. Tyr385 makes for some sterical
restrictions of this side of the binding site so a small
substituent of the phenyl group makes for better binding.
Degrees of freedom are also important for the binding. The
central ring of the coxibs decides the orientation of the
aromatic rings and thereby the binding to COX enzyme
even though it often has no electrostatic interactions with any
of the amino acid residues. The high lipophilicity of the
active site does require low polarity of the central scaffold of
the coxibs.

Mechanism of binding
Studies on the binding mechanism of selective COX-2 inhibitors
show that they have two reversible steps with both COX-1
and COX-2 but the selectivity for COX-2 is due to another
step that is slow and irreversible and is only seen in the
inhibition of COX-2 but not COX-1. The irreversible step has
been attributed to the presence of the sulphonamide (or

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 sulphone) that fits into the side pocket of COX-2. This has
been studied using SC-58125 (an analogue of celecoxib)
and mutated COX-2 where the valine 523 residue was
replaced by isoleucine 523. The irreversible inhibition did not
happen but reversible inhibition was noticed. A model has
been made to explain this three step mechanism behind the
inhibitory effects of selective COX-2 inhibitors. The first step
accounts for the contact of the inhibitor with the gate of the
hydrophobic channel (called the lobby region). The second
step could account for the movement of the inhibitor from the
lobby region to the active site of the COX enzyme. The last
step probably represents repositioning of the inhibitor at the
active site which leads to strong interactions of the
phenylsulphonamide or phenylsulphone group of the inhibitor
and the amino acids of the side pocket.

COX-2
Another enzyme, cyclooxygenase-2 (COX-2), also produces
these chemical messenger molecules, but the COX-2
enzyme is located specifically in areas of the body that are
responsible for inflammation and not in the stomach. When
the COX-2 enzyme is blocked, inflammation is reduced.
Since the COX-2 enzyme does not play a role in the normal
function of the stomach, medications that selectively block
COX-2 do not present the risk of injuring the stomach that
medications also blocking COX-1 can.

Newly developed drugs that selectively block the COX-2 enzyme

are called COX-2 inhibitors. Blocking this enzyme impedes
the production of the prostaglandins that cause the pain and
swelling of arthritis inflammation. The common anti-
inflammatory drugs (like aspirin, ibuprofen, and naproxen)
are all non-selective and act by blocking the action of both
the COX-1 and COX-2 enzymes.

The COX-2 inhibitors represent a newer class of anti-inflammatory

drugs that do not affect COX-1, but selectively block only
COX-2. This selective action provides the benefits of
reducing inflammation without the increased risk of stomach
irritation, ulceration, and bleeding. A major advantage of the
COX-2 inhibitors over traditional non-selective COX-1 and
COX-2 NSAIDs (nonsteroidal anti-inflammatory drugs)

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 lies in the fact that they are easier on the stomach.
Therefore, they are generally considered safer for patients
with a history of stomach (gastrointestinal) problems.
Another particular advantage of COX-2 inhibitors is that they
do not impair the normal function of an important blood
clotting element called platelets. As a result, they may be
used in patients taking blood thinning medications, such as
warfarin (Coumadin), and they may be used in and around
surgical procedures without an increased risk of bleeding

Example of COX-2 inhibitors

CELEBREX
Celecoxib is a non-steroidal anti-inflammatory drug (NSAID)
used in the treatment of osteoarthritis, rheumatoid
arthritis, acute pain, painful menstruation and menstrual
symptoms, and to reduce numbers of colon and rectum
polyps in patients with familial adenomatous polyposis. It
is marketed by Pfizer. It has the brand name Celebrex and
Celebra (in other countries) for arthritis and Onsenal for
polyps. Celecoxib is available by prescription in capsule
form.

(celecoxib) is chemically designated as 4-[5-(4-methylphenyl)-3-

(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide and is
a diaryl-substituted pyrazole. It has the following chemical
structure

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The empirical formula for celecoxib is C 17H14F3N3O2S, and the
molecular weight is 381.38.

CELEBREX oral capsules contain either 50 mg, 100 mg, 200 mg

or 400 mg of celecoxib. The inactive ingredients in
CELEBREX capsules include: croscarmellose sodium, edible
inks, gelatin, lactose monohydrate, magnesium stearate,
povidone and sodium lauryl sulfate.

Mode of action

Celecoxib is a highly selective COX-2 inhibitorand primarily

inhibits this isoform of cyclooxygenase (inhibition of
prostaglandin production), whereas traditional NSAIDs inhibit
both COX-1 and COX-2.Celecoxib is approximately 7.6 times
more selective for COX-2 inhibition over COX-1. In theory,
this selectivity allows celecoxib and other COX-2 inhibitors to
reduce inflammation (and pain) while minimizing
gastrointestinal adverse drug reactions (e.g. stomach
ulcers) that are common with non-selective NSAIDs.

It inhibit cyclo-oxygenase 2 only without affect cyclo-oxygenase 1

cox 1 inhibit prostaglandin and thromboxan but cox 2 inhibit
prostaglandin only so inhibition of cox 2 only will inhibit PGs
synthesis without affecting Thromboxan so it hasn't any
effect on platlet aggregation or blood clotting

Side effect

Gastrointestinal ADRs

In theory the COX-2 selectivity should result in a significantly lower

incidence of gastrointestinal ulceration than traditional
NSAIDs. The main body of evidence touted to support this
theory were the preliminary (6 month) results of the
Celecoxib Long-term Arthritis Safety Study (CLASS) as
published in 2000, which demonstrated a significant
reduction in the combination of symptomatic ulcers plus ulcer
complications in those taking celecoxib versus ibuprofen or
diclofenac, provided they were not on aspirin (Silverstein et
al, 2000). However, this was not significant at 12 months (full
study length). It should be noted that this study used a very
high dose of Celebrex, 800 mg daily (400 mg twice a day).

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Allergy

Celecoxib contains a sulfonamide moiety and may cause allergic

reactions in those allergic to other sulfonamide-containing
drugs. This is in addition to the contraindication in patients
with severe allergies to other NSAIDs.

Risk of heart attack and stroke

There has been much concern about the possibility of increased

risk for heart attack and stroke in users of NSAID drugs,
particularly COX-2 selective NSAIDs such as celecoxib,
since the withdrawal of the COX-2 inhibitor rofecoxib (Vioxx)
in 2004. Like all NSAIDs on the U.S. market, celecoxib
carries an FDA-mandated "black box warning" for
cardiovascular and gastrointestinal risk. In February 2007,
the American Heart Association warned that celecoxib
should be used "as a last resort on patients who have heart
disease or a risk of developing it", and suggested that
paracetamol (acetaminophen), or certain older NSAIDs,
such as naproxen, may be safer choices for pain relief in
these patients.

The cardiovascular risks of celecoxib are controversial, with

apparently contradictory data produced from different clinical
trials. In December 2004, "APC," the first of two trials of
celecoxib for colon cancer prevention, found that long-term
(33 months) use of high-dose Celebrex (400 and 800mg
daily) demonstrated an increased cardiovascular risk
compared with placebo. A similar trial, named PreSAP, did
not demonstrate an increased risk. Still, the APC trial,
combined with the recent Vioxx findings, suggested that
there might be serious cardiovascular risks specific to the
COX-2 inhibitors. On the other hand, a large Alzheimers
prevention trial, called ADAPT, was terminated early after
preliminary data suggested that the nonselective NSAID
naproxen, but not celecoxib, was associated with increased
cardiovascular risk. In April 2005, after an extensive review
of data, the FDA concluded that it was likely "that there is a
'class effect' for increased CV risk for all NSAIDs." Two
studies on the cardiovascular risks of celecoxib and other
NSAIDs were meta-analyses, published in 2006. The first of
these, published in the British Medical Journal, looked at

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 the incidence of cardiovascular events in all previous
randomized controlled trials of COX-2 inhibitors, as well as
some trials of other NSAIDs. The authors concluded that a
significant increased risk did exist for celecoxib, as well as
some other selective and nonselective NSAIDS. However,
the increased cardiovascular risk in celecoxib was only noted
at daily doses of 400 mg or greater. A second meta-analysis
published in the Journal of the American Medical
Association, which included observational rather than
randomized studies (mostly at lower doses) did not find an
increased cardiovascular risk of celecoxib vs placebo.

To more conclusively establish the true cardiovascular risk profile

of celecoxib, Pfizer has agreed to fund a large, randomized
trial specifically designed for that purpose. The trial, centered
at the Cleveland Clinic, has a planned enrollment of 20,000
high-risk patients. Celecoxib will be compared to the non-
selective NSAIDS naproxen and ibuprofen. Since all
patients have arthritis, ethical considerations make it difficult
to have a placebo group. This trial has just begun enrollment
according to the Clinical Trials database, and is not
scheduled to be completed until 2010. Ultimately, this trial
will help answer the question as to whether Celebrex has a
riskier cardiovascular profile compared to naproxen or
ibuprofen.

Valdecoxib

4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide

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Valdecoxib is a prescription drug used in the treatment of
osteoarthritis, rheumatoid arthritis, and painful
menstruation and menstrual symptoms. It is classified as a
nonsteroidal anti-inflammatory drug, or NSAID, and should
not be taken by anyone allergic to these types of
medications.

Valdecoxib was manufactured and marketed under the brand

name Bextra by G. D. Searle & Company. It was approved
by the United States Food and Drug Administration on
November 20, 2001, and was available by prescription in
tablet form until 2005, when it was removed from the market
due to concerns about possible increased risk of heart
attack and stroke.

Mode of action

Valdecoxib is a nonsteroidal anti-inflammatory drug (NSAID)

that exhibits anti-inflammatory, analgesic and antipyretic
properties in animal models. The mechanism of action is
believed to be due to inhibition of prostaglandin synthesis
primarily through inhibition of cyclooxygenase-2 (COX-2).
At therapeutic plasma concentrations in humans valdecoxib
does not inhibit cyclooxygenase-1 (COX-1).

Side-effects and withdrawal

On April 7, 2005, Pfizer withdrew Bextra from the U.S. market on

recommendation by the FDA, citing an increased risk of
heart attack and stroke and also the risk of a serious,
sometimes fatal, skin reaction. This was a result of recent
attention to prescription NSAIDs, such as Merck's Vioxx.
Other reported side-effects were angina and Stevens-
Johnson syndrome.

Pfizer first acknowledged cardiovascular risks associated with

Bextra in October 2004. The American Heart Association
soon after was presented with a report indicating patients
using Bextra while recovering from heart surgery were 2.19
times more likely to suffer a stroke or heart attack than those
taking placebos.

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Recently in a large study published in JAMA 2006, valdecoxib
appears less adverse for renal (kidney) disease and heart
arrhythmia compared to Vioxx, however elevated renal risks
were slightly suggested.

Etoricoxib

5-chloro-2-(6-methylpyridin-3-yl)-3-(4-
methylsulfonylphenyl)pyridine

Etoricoxib (brand name Arcoxia worldwide; also Algix and Tauxib in

Italy) is a COX-2 selective inhibitor (approx. 106.0 times
more selective for COX-2 inhibition over COX-1) from Merck
& Co. Doses are 60, 90 mg/day for chronic pain and
120 mg/day for acute pain. Currently it is approved in more
than 60 countries worldwide but not in the US, where the
Food and Drug Administration (FDA) requires additional
safety and efficacy data for etoricoxib before it will issue
approval. Current therapeutic indications are: treatment of
rheumatoid arthritis, osteoarthritis, ankylosing
spondylitis, chronic low back pain, acute pain and gout.
Note that approved indications differ by country.

Mode of action

Like any other COX-2 selective inhibitor Etoricoxib selectively

inhibits isoform 2 of cyclo-oxigenase enzyme (COX-2). This
reduces prostaglandins (PGs) generation from arachidonic
acid.

Like any other COX-2 selective inhibitor, Etoricoxib selectively

inhibits isoform 2 of cyclo-oxigenase enzyme (COX-2). This
reduces the generation of prostaglandins (PGs) from
arachidonic acid. Among the different functions exerted by

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 PGs, their role in the inflammation cascade should be
highlighted. COX-2 selective inhibitor (aka "COXIB")
showed less marked activity on type 1 cycloxigenase
compared to traditional non-steroidal anti-inflammatory
drugs (NSAID). This reduced activity is the cause of reduced
gastrointestinal toxicity, as demonstrated in several large
clinical trials performed with different COXIB (see below links
on NEJM and The Lancet).

Some clinical trials and meta-analysis showed that treatment with

some COXIBs (in particular Vioxx, rofecoxib) led to
increased incidence of adverse cardiovascular events
compared to placebo. Because of these results, some
molecules were withdrawn from the market (Rofecoxib,
September 2004 and Valdecoxib, April 2005). In addition,
the FDA and EMEA (USA and European Community Health
Authorities respectively) started a revision process of the
entire class of both NSAID and COX-2 inhibitors.

Lumiracoxib

{2-[(2-chloro-6-fluorophenyl)amino]-5-methylphenyl}
acetic acid

Lumiracoxib (rINN) is a COX-2 selective inhibitor non-steroidal

anti-inflammatory drug, manufactured by Novartis and still
sold in few countries, including Mexico, Colombia, and the
Dominican Republic, under the trade name Prexige
(sometimes misquoted as "Prestige" by the media).

Lumiracoxib has several distinctive features. Its structure is

different from that of other COX-2 inhibitors, such as
celecoxib: lumiracoxib is an analogue of diclofenac (one
chlorine substituted by fluorine, the phenylacetic acid has
another methyl group in meta position), making it a member
of the arylalkanoic acid class of NSAIDs; it binds to a
different site on the COX-2 receptor than do other COX-2
inhibitors; it is the only acidic coxib; and has the highest

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 COX-2 selectivity of any NSAID. Since its original approval,
lumiracoxib has been withdrawn from the market in several
countries, mostly due to hepatotoxicity concerns. It has
never been approved for use in the United States

Mode of action

The mechanism of action of lumiracoxib is due to inhibition of

prostaglandin synthesis via inhibition of cyclooygenase-2
(COX-2). Lumiracoxib does not inhibit COX-1 at therapeutic
concentrations.

side effect

Dizziness.

Headache.

Flu-like symptoms.

Disturbances of the gut, such as abdominal pain, constipation,

diarrhoea, indigestion, nausea, vomiting, flatulence.

Fatigue.

Swelling of the legs and ankles due to fluid retention (oedema).

Depression.

Difficulty sleeping (insomnia).

Anxiety.

Pins and needles or numb sensations.

Sensation of ringing or other noise in the ears (tinnitus).

Fainting.

Visual disturbances.

Shortness of breath.

Nosebleeds (epistaxis).

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Muscle cramps.

Chest pain.

Skin reactions such as rash and itch.

Ulceration or bleeding of the stomach or intestine.

Heart attack or stroke.

Liver, kidney or blood disorders

Rofecoxib

4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one

Rofecoxib is a nonsteroidal anti-inflammatory drug (NSAID)

marketed by Merck & Co. to treat osteoarthritis, acute
pain conditions, and dysmenorrhoea. Rofecoxib was
approved as safe and effective by the Food and Drug
Administration (FDA) on May 20, 1999, and was
subsequently marketed under the brand name Vioxx, Ceoxx
and Ceeoxx.

Rofecoxib gained widespread acceptance among physicians

treating patients with arthritis and other conditions causing
chronic or acute pain. Worldwide, over 80 million people
were prescribed rofecoxib at some time.

On September 30, 2004, Merck voluntarily withdrew rofecoxib

from the market because of concerns about increased risk of
heart attack and stroke associated with long-term, high-
dosage use. Rofecoxib was one of the most widely used
drugs ever to be withdrawn from the market.

Mode of action

Cyclooxygenase (COX) has two forms, called COX-1 and COX-2.

COX-1 mediates the synthesis of prostaglandins

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 responsible for protection of the stomach lining, while COX-2
mediates the synthesis of prostaglandins responsible for pain
and inflammation. By creating selective NSAIDs that inhibit
COX-2, but not COX-1, the same pain relief as traditional
NSAIDs is offered, but with greatly reduced risk of fatal or
debilitating peptic ulcers. Rofecoxib is such a selective COX-
2 inhibitor or coxib (CycloOXygenase-2 InhiBitors).

Others include Merck's etoricoxib (Arcoxia), Pfizers celecoxib

(Celebrex) and valdecoxib (Bextra). Interestingly, at the time
of its withdrawal, rofecoxib was the only coxib with clinical
evidence of its superior gastrointestinal adverse effect profile
over conventional NSAIDs. This was largely based on the
VIGOR study, which compared the efficacy and adverse
effect profiles of rofecoxib and naproxen.

Adverse drug reactions

Aside from the reduced incidence of gastric ulceration, rofecoxib

exhibits a similar adverse effect profile to other NSAIDs.
Rofecoxib, however, does appear to increase the risk of
adverse cardiovascular events.

The chief mechanism proposed to explain rofecoxib's cardiotoxicity

is the suppression of prostacyclin, an anti-clotting agent in
the blood (Fitzgerald, 2004). COX-2 plays a role in the
production of prostacyclin. Because Vioxx inhibits the COX-2
enzyme, prostacyclin production can decrease in endothelial
cells and lead to an inefficiency in declumping and
vasodilatation. Merck, however, argues that there was no
effect on prostacyclin production in blood vessels in animal
testing. Other researchers have speculated that the
cardiotoxicity may be associated with maleic anhydride
metabolites formed when rofecoxib becomes ionized under
physiological conditions.

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Reference
^ Tacconelli S, Capone ML, Patrignani P (2004). "Clinical
pharmacology of novel selective COX-2 inhibitors". Curr
Pharm Des 10 (6): 589601. PMID 14965322,
http://www.bentham-direct.org/pages/content.php?
CPD/2004/00000010/00000006/0003B.SGM.

^ Urgent medicine recall - Lumiracoxib (PREXIGE)

^ http://hugin.info/134323/R/1156327/223186.pdf

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^ Withdrawal of Market Authorization for Prexige

^ Media releases

^ http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-
4090B1_33_GG-FDA-Tab-U.pdf

^ Medicines Regulator cancels registration of anti inflammatory

drug, Lumiracoxib, Therapeutic Goods Administration, 2007-
08-11. Retrieved on 2007-08-11

^ http://www.tga.gov.au/media/2007/070811-lumiracoxib.htm]
[http://www.tga.gov.au/recalls/2007/lumiracoxib.htm

^ NZ regulators ban arthritis drug - 21 Aug 2007 - Pharmaceuticals

news - NZ Herald

^
http://www.novartis.ca/downloads/en/letters/prexige_fact_20
071003_e.pdf

^ Press release: European Medicines Agency recommends

withdrawal of the marketing authorisations for lumiracoxib-
containing medicines, 13 December 2007

^ Abs-Cbn Interactive, DOH recalls lumiracoxib, sets two-week

deadline

^ "Anvisa cancela registro do Prexige; consumidor deve substituir

medicamento" (in Portuguese), Folha de S. Paulo (July 22,
2008). Retrieved on 22 July 2008.

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