Description
Celecoxib is a nonsteroidal antiinflammatory drug (NSAID) first
launched as Celebrex in the US for the treatment of symptoms in patients with
rheumatoid arthritis (RA) and osteoarthritis (OA). Celecoxib belongs to a new
class of 1, 5-diarylpyrazoles and can be synthesized by heat-promoted
heterocyclization of a trifiuoro-l,3-dione with appropriate arylhydrazine.
Celecoxib is a highly selective inhibitor of COX-2, the inducible form of
cyclooxygenase expressed during inflammatory processes; it does not block the
constitutive form COX-1, thus suppressing the gastric and intestinal toxicity of
most non-selective NSAIDs. The potency ratio COX1/COX2 on purified human
enzymes was about 400. In several in vivo models of acute and chronic
inflammation, Celecoxib demonstrated potent antiinflammatory activity without
affecting gastric or urinary prostaglandin PGE2. In several clinical studies
performed with patients suffering from osteoarthritis or rheumatoid arthritis,
Celecoxib was shown to be well tolerated and to relieve pain and inflammation more efficiently compared with other standard NSAIDs; the gastrointestinal
safety profile was significantly better than that of other NSAIDs. Interestingly,
Celecoxib was approved for another indication in patients with familial adenomatous polyposis (FAP). A six-month clinical trial
demonstrated a 28% reduction in the number of colorectal polyps with
Celecoxib, compared to a 5% reduction with placebo.
Chemical Properties
White to Pale Yellow Solid
Uses
A selective cyclooxygenase-2 (COX-2) inhibitor. Anti-inflammatory. Used in treatment of familial adenomatous polyposis
Uses
expectorant, gastric stimulant, insecticide
Uses
For relief and management of osteoarthritis (OA), rheumatoid arthritis (RA), juvenile rheumatoid arthritis (JRA), ankylosing spondylitis, acute pain, primary dysmenorrhea and oral adjunct to usual care for patients with familial adenomatous polyposis
Definition
ChEBI: Celecoxib is a member of the class of pyrazoles that is 1H-pyrazole which is substituted at positions 1, 3 and 5 by 4-sulfamoylphenyl, trifluoromethyl and p-tolyl groups, respectively. A cyclooxygenase-2 inhibitor, it is used in the treatment of arthritis. It has a role as a cyclooxygenase 2 inhibitor, a geroprotector, a non-steroidal anti-inflammatory drug and a non-narcotic analgesic. It is a member of toluenes, a sulfonamide, a member of pyrazoles and an organofluorine compound.
Indications
Celecoxib is indicated for the treatment of osteoarthritis
and rheumatoid arthritis. Its use is contraindicated
in individuals with hypersensitivity to sulfonamides
or other NSAIDs. It should be used with
caution in persons with hepatic disease. Interactions occur
with other drugs that induce CYP2C9 (e.g. rifampin rifampin)
or compete for metabolism by this enzyme (e.g.
fluconazole, leflunomide). The most common adverse
reactions to celecoxib are mild to moderate GI effects
such as dyspepsia, diarrhea, and abdominal pain.
Serious GI and renal effects have occurred rarely.
Manufacturing Process
4-(5-(4-Methylphenyl)-3-trifluoromethyl-N-pyrazol-1-yl)benzenesulfonamide
To a solution of ethyl trifluoroacetate (1.90 ml, 16.0 mmol) in 7 ml of methyl
tert-butyl ether was added 25% NaOMe (3.62 ml, 16.8 mmol). Next 4-
chloroaceteophenone (2.08 ml, 16.0 mmol) in 2 ml of methyl tert-butyl ether
was added. The mixture was stirred at room temperature overnight. To above
solution was added 100 ml of 90% EtOH, followed by 4 N HCl (4.0 ml, 16
mmol) and 4-sulphonamidophenylhydrazine hydrochloride (3.58 g, 16 mmol).
The mixture was heated to reflux for 3 hours. The mixture was concentrated.
When 30 ml of water was added, a solid formed. The solid was filtered and
washed with 20 ml of 60% EtOH to give 4.50 g of white solid. The filtrate was
evaporated and taken up in ethyl acetate (100 ml), washed with saturated
NaHCO3, and brine, dried over MgSO4, and concentrated. Heptane was added
at boiling point of the mixture. After cooling down to 0°C, 1.01 g more
product was obtained. The combined yield of the 4-(5-(4-methylphenyl)-3-
trifluoromethyl-N-pyrazol-1-yl)benzenesulfonamide (Celecoxib) was 86%.
Brand name
Celebrex (Searle).
Therapeutic Function
Antiinflammatory
General Description
Celecoxib (Celebrex) was the first selective COX-2 inhibitordrug introduced into the market in 1998 for use in thetreatment of RA, OA, acute pain, and menstrual pain. Thereal benefit is that it has caused fewer GI complicationswhen compared with other conventional NSAIDs. It hasalso been approved for reducing the number of adenomatouscolorectal polyps in familial adenomatous polyposis (FAP).Celecoxib is well absorbed and undergoes rapid oxidativemetabolism via CYP2C9 to give its inactive metabolites. Thus, a potential drug interaction exists betweencelecoxib and warfarin because the active isomer ofwarfarin is primarily degraded by CYP2C9.
Biological Activity
Selective cyclooxygenase-2 (COX-2) inhibitor (IC 50 values are 15 and 0.04 μ M for COX-1 and COX-2 respectively). Anti-inflammatory with shorter plasma half-life in vivo than SC 58121 (5-(4-Fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole ). Displays chemopreventive activity in in vivo tumor models.
Biochem/physiol Actions
Celecoxib is a non-steroidal, anti-inflammatory drug (NSAID) and a cyclooxygenase-2 (COX-2) selective inhibitor. Celecoxib is at least 10-20 times more selective for COX-2 over COX-1.
Clinical Use
Celecoxib is currently indicated for the relief of signs and symptoms of osteoarthritis and rheumatoid arthritis and to
reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis as an adjunct to usual care.
Celecoxib is synthesized by condensing 4-methyl-acetophenone and ethyltrifluoroacetate with sodium methoxide and
the resulting butanedione derivative cyclized with 4-hydrazinophenylsulfonamide. It was the first NSAID to be
marketed as a selective COX-2 inhibitor.
in vitro
celecoxib not only reduced the production of pge2 but also inhibited the downstream effects of pge2. celecoxib blocked migration and invasion of a549 cells increased by pge2 in the wound healing and transwell assays. additionally, celecoxib reduced mmp9 mrna expression which was increased by pge2. moreover, celecoxib enhanced e-cadherin mrna expression which was inhibited by pge2 [2].
in vivo
celecoxib inhibited the increase in metastases of a549 cells and significantly reduced the increase in pge2 plasma level in mice receiving unilateral pneumonectomy [2].
Drug interactions
Potentially hazardous interactions with other drugs
ACE inhibitors and angiotensin-II antagonists:
antagonism of hypotensive effect; increased risk of
nephrotoxicity and hyperkalaemia.
Analgesics: avoid concomitant use of 2 or more
NSAIDs, including aspirin (increased side effects);
avoid with ketorolac (increased risk of side effects
and haemorrhage).
Antibacterials: possibly increased risk of convulsions
with quinolones; concentration reduced by
rifampicin
Anticoagulants: effects of coumarins and
phenindione enhanced; possibly increased risk of
bleeding with heparins, dabigatran and edoxaban -
avoid long term use with edoxaban.
Antidepressants: increased risk of bleeding with
SSRIs and venlaflaxine.
Antidiabetic agents: effects of sulphonylureas
enhanced
Antiepileptics: possibly increased phenytoin
concentration.
Antifungals: if used with fluconazole, halve the dose
of celecoxib.
Antivirals: increased risk of haematological toxicity
with zidovudine; concentration possibly increased by
ritonavir.
Ciclosporin: may potentiate nephrotoxicity
Cytotoxics: reduced excretion of methotrexate;
increased risk of bleeding with erlotinib.
Diuretics: increased risk of nephrotoxicity;
antagonism of diuretic effect; hyperkalaemia with
potassium-sparing diuretics.
Lithium: excretion decreased.
Pentoxifylline: possibly increased risk of bleeding
Tacrolimus: increased risk of nephrotoxicity.
Metabolism
Celecoxib is excreted in the urine and feces primarily as inactive metabolites, with less than 3% of an
administered dose being excreted as unchanged drug. Metabolism occurs primarily in the liver by CYP2C9 and
involves hydroxylation of the 4-methyl group to the primary alcohol, which is subsequently oxidized
to its corresponding carboxylic acid, the major metabolite (73% of the administered dose). The carboxylic
acid is conjugated, to a slight extent, with glucuronic acid to form the corresponding glucuronide. None of the
isolated metabolites have been shown to exhibit pharmacological activity as inhibitors of either COX-1 or COX-2.
Celecoxib also inhibits CYP2D6; thus, the potential of celecoxib to alter the pharmacokinetic profiles of other drugs
inhibited by this isoenzyme exists. Celecoxib, however, does not appear to inhibit other CYP isoforms, such as
CYP2C19 or CYP3A4. Other drug interactions related to the metabolic profile of celecoxib have been noted,
particularly with other drugs that inhibit CYP2C.
References
1) Penning . (1997), Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-58635, celecoxib); J. Med. Chem., 40 1347
2) DeWitt et al. (1999), Cox-2-selective inhibitors: the new super aspirins; Mol. Pharmacol., 55 625
3) Harris et al. (2000), Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor; Cancer Res., 60 2101
4) Koki and Masferrer et al. (2002), Celecoxib: a specific COX-2 inhibitor with anticancer properties; Cancer Control, 9 28
