Celecoxib

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Celecoxib
Skeletal formula of celecoxib
Space-filling model of celecoxib
Systematic (IUPAC) name
4-[5-(4-Methylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide
Clinical data
Trade namesCelebrex
AHFS/Drugs.commonograph
MedlinePlusa699022
Licence dataUS FDA:link
Pregnancy cat.B3 (AU) C (US)
Legal statusPrescription Only (S4) (AU) -only (US)
RoutesOral
Pharmacokinetic data
Bioavailability40%
Protein binding97% (mainly to serum albumin)
MetabolismHepatic (mainly CYP2C9)
Half-life~11 h
ExcretionRenal 27%, faecal 57%
Identifiers
CAS number169590-42-5 YesY
ATC codeL01XX33 M01AH01
PubChemCID 2662
DrugBankDB00482
ChemSpider2562 YesY
UNIIJCX84Q7J1L YesY
KEGGD00567 YesY
ChEBICHEBI:41423 YesY
ChEMBLCHEMBL118 YesY
Chemical data
FormulaC17H14F3N3O2S 
Mol. mass381.373 g/mol
 YesY (what is this?)  (verify)
 
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Celecoxib
Skeletal formula of celecoxib
Space-filling model of celecoxib
Systematic (IUPAC) name
4-[5-(4-Methylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide
Clinical data
Trade namesCelebrex
AHFS/Drugs.commonograph
MedlinePlusa699022
Licence dataUS FDA:link
Pregnancy cat.B3 (AU) C (US)
Legal statusPrescription Only (S4) (AU) -only (US)
RoutesOral
Pharmacokinetic data
Bioavailability40%
Protein binding97% (mainly to serum albumin)
MetabolismHepatic (mainly CYP2C9)
Half-life~11 h
ExcretionRenal 27%, faecal 57%
Identifiers
CAS number169590-42-5 YesY
ATC codeL01XX33 M01AH01
PubChemCID 2662
DrugBankDB00482
ChemSpider2562 YesY
UNIIJCX84Q7J1L YesY
KEGGD00567 YesY
ChEBICHEBI:41423 YesY
ChEMBLCHEMBL118 YesY
Chemical data
FormulaC17H14F3N3O2S 
Mol. mass381.373 g/mol
 YesY (what is this?)  (verify)

Celecoxib INN (/sɛlɨˈkɒksɪb/ SE-lə-KOK-sib) is a sulfonamide nonsteroidal anti-inflammatory drug (NSAID) and selective COX-2 inhibitor 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 people with familial adenomatous polyposis.

Side effects include a 37% increase in incidence of major vascular events, which include non-fatal myocardial infarction, non-fatal stroke or death from a vascular cause.[1] Additionally there is an 81% increase in incidence of upper gastrointestinal complications which include perforations, obstructions or bleeds.[1]

It is marketed by Pfizer. It is known under the brand name Celebrex or Celebra for arthritis and Onsenal for polyps. Celecoxib is available by prescription in capsule form.

Medical uses[edit]

Celecoxib is used for osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation, ankylosing spondylitis, and to reduce the number of colon and rectal polyps in patients with familial adenomatous polyposis.

For post operative pain it is more or less equal to ibuprofen.[2] For pain relief it is similar to paracetamol (acetaminophen).[3] And in osteoarthritis acetaminophen is the first line treatment for OA.[4][5]

It was originally intended to relieve pain while minimizing the gastrointestinal adverse effects seen with conventional NSAIDs. In practice, its primary indication is in patients who need regular and long-term pain relief; there is probably no advantage to using celecoxib for short term or acute pain relief over conventional NSAIDs, except in the situation where nonselective NSAIDs or aspirin cause cutaneous reactions (urticaria or "hives").

Adverse effects[edit]

Anaphylactoid reactions: Contrary to the package insert and many other reviews the risk of Anaphylactoid reactions with Cox 2 inhibitors is decreased. Particularly Aspirin Triad Asthmatics tolerate highly selective Cox 2 inhibitors. (Stevenson DD et al. J Allergy Clin Immunol 2000;105;s273.) without exception. Celecoxib is actually safer than acetaminophen in Asprin Triad Asthma.

Patients with prior history of ulcer disease or GI bleeding require special precaution. Moderate to severe hepatic impairment or GI toxicity can occur with or without warning symptoms in patients treated with NSAIDs.

Allergy[edit]

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. However, it has a low (reportedly 4%) chance of inducing cutaneous reactions among persons who have a history of such reactions to aspirin or nonselective NSAIDs.

Drug interactions[edit]

Celecoxib is predominantly metabolized by cytochrome P450 2C9. Caution must be exercised with concomitant use of 2C9 inhibitors, such as fluconazole, which can greatly elevate celecoxib serum levels. In addition, celecoxib may increase the risk of renal failure with angiotensin converting enzyme-inhibitors, such as lisinopril, and diuretics, such as hydrochlorothiazide.[8]

Pregnancy[edit]

In the US FDA's pregnancy categories, the drug is category C prior to 30 weeks gestation, and category D starting at 30 weeks gestation.[8]

Heart attack and stroke[edit]

The coxibs (which includes celecoxib) increase the risk of major cardiovascular problems by about 37%.[1] The NSAID naproxen or paracetamol (acetaminophen) appears to be safer.[1]

The COX-2 inhibitor rofecoxib (Vioxx) was removed from the market in 2004 due to its risk. Like all NSAIDs on the US market, celecoxib carries an FDA-mandated "black box warning" for cardiovascular and gastrointestinal risk. In February 2007, the American Heart Association warned that with respect to "patients with a prior history of or at high risk for cardiovascular disease... use of COX-2 inhibitors for pain relief should be limited to patients for whom there are no appropriate alternatives, and then, only in the lowest dose and for the shortest duration necessary."[9]

In 2005, a study published in the Annals of Internal Medicine found that cardiovascular effects of COX-2 inhibitors differ, depending on the drug.[10] Other COX-2-selective inhibitors, such as rofecoxib, have significantly higher myocardial infarction rates than celecoxib.[11] In April 2005, after an extensive review of data, the FDA concluded it was likely "that there is a 'class effect' for increased CV risk for all NSAIDs".[12] In a 2006 meta-analysis of randomized control studies, the cerebrovascular events associated with COX-2 inhibitors were examined, but no significant risks were found when compared to nonselective NSAIDs or placebos.[13]

Pharmacology[edit]

Celecoxib is a highly selective COX-2 inhibitor and primarily inhibits this isoform of cyclooxygenase (and thus causes inhibition of prostaglandin production), whereas nonselective NSAIDs (such as aspirin, naproxen, and ibuprofen) inhibit both COX-1 and COX-2. COX-1, traditionally defined as a constitutively expressed "housekeeping" enzyme, is the only isoenzyme found in platelets, and plays a role in the protection of the gastrointestinal mucosa, renal hemodynamics, and platelet thrombogenesis.[14][15] COX-2, on the contrary, is extensively expressed in cells involved in inflammation and is upregulated by bacterial lipopolysaccharides, cytokines, growth factors, and tumor promoters.[14][16] Celecoxib is approximately 10-20 times more selective for COX-2 inhibition over COX-1.[15][17] It binds with its polar sulfonamide side chain to a hydrophilic side pocket region close to the active COX-2 binding site.[18] 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 nonselective NSAIDs.

Celecoxib inhibits COX-2 without affecting COX-1. COX-1 is involved in synthesis of prostaglandins and thromboxane, but COX-2 is only involved in the synthesis of prostaglandin. Therefore, inhibition of COX-2 inhibits only prostaglandin synthesis without affecting thromboxane, so offers no cardioprotective effects of nonselective NSAIDs.

Fabricated efficacy studies[edit]

On March 11, 2009, Scott S. Reuben, former chief of acute pain at Baystate Medical Center, Springfield, Massachusetts, revealed that the data for 21 studies he had authored for the efficacy of the drug (along with others such as Vioxx) had been fabricated. The analgesic effects of the drugs had been exaggerated. Reuben was also a former paid spokesperson for Pfizer. None of the retracted studies were submitted to either the US Food and Drug Administration or the European Union's regulatory agencies prior to the drug's approval. Pfizer issued a public statement declaring, "It is very disappointing to learn about Dr. Scott Reuben's alleged actions. When we decided to support Dr. Reuben's research, he worked for a credible academic medical center and appeared to be a reputable investigator."[19][20]

Medicinal chemistry[edit]

Synthesis[edit]

The synthesis of celecoxib was first described in 1997 by a team of researchers at Searle Research and Development. It is synthesized by a Claisen condensation reaction of an acetophenone with N-(trifluoroacetyl)imidazole catalyzed by the strong base, sodium bis(trimethylsilyl)amide to produce a 1,3-dicarbonyl adduct.[21] Condensation of the diketone with (4-sulfamoylaphenyl)hydrazine produces the 1,5-diarylpyrazole drug moiety.

Synthesis of celecoxib.gif

Structure-activity relationship[edit]

Monosubstituted 1,5-diarylpyrazoles.jpg
Enzyme data for monosubstituted 5-aryl analogs.jpg
Enzyme data for 4-substituted analogs.jpg
In vitro cox-I and cox-II enzyme data for disubstituted 5-aryl analogs.jpg

The Searle research group found the two appropriately substituted aromatic rings must reside on adjacent positions about the central ring for adequate COX-2 inhibition. Various modifications can be made to the 1,5-diarylpyrazole moiety to deduce the structure-activity relationship of celecoxib.[21] A para-sulfamoylphenyl at position 1 of the pyrazole was found to have a higher potency for COX-2 selective inhibition than a para-methoxyphenyl (see structures 1 and 2, below). In addition, a 4-(methylsulfonyl)phenyl or 4-sulfamoylphenyl is known to be necessary for COX-2 inhibition. For instance, replacing either of these entities with a –SO2NHCH3 substituent diminishes COX-2 inhibitory activity as noted with a very high inhibitory concentration-50 (see structures 3 - 5). At the 3-position of the pyrazole, a trifluoromethyl or difluoromethyl provides superior selectivity and potency compared to a fluoromethyl or methyl substitution (see structures 6 – 9).[21]

The fourth position of the pyrazole is readily affected by steric hindrance such that increasing the bulkiness of the substitution starkly decreases the potency. For example, by progressively increasing the size of R1, from a methyl to propyl, the potency for COX-2 inhibition decreases especially with moieties larger than an ethyl (see structures 10-12). In addition, incorporating a halo-atom at this position provides significantly potent COX-2 inhibition (see structures 13 and 14). While it is known there must be an aromatic system at the fifth position of the pyrazole, optimizing this substituent is difficult since it is not known what combination of modifications will provide the highest potency and selectivity due to the flexible nature of the 5-aryl system. It was found that substitutions at either the para (4-substitution) or ortho (2-substitution) sites have higher potency than meta (3-substitution) sites (see structures 15-17).

Electron withdrawing groups, such as –CN, at these positions have poor COX-1 and COX-2 inhibition; however, electron donating groups, such as methoxyl, have substantial COX-1 and COX-2 inhibitory effects which makes them inefficient as a COX-2 selective inhibitor (see structures 18 and 19 ). The strong COX-1 inhibition of the para-methoxyl can be corrected by substituting a halo-atom at the alpha position. For instance, the introduction of a 3-fluoro or 3-chloro decreases COX-1 inhibition by 43- and 33-folds, respectively (see structures 20 and 21). It is necessary to consider the steric hindrance created by a para-substitution of the 5-aromatic system. Consider the COX-2 inhibitory capacity of the 4-methyl and 4-ethyl modifications: 4-methyl can inhibit COX-2 such that the IC50 is 0.040 μM while that of the 4-ethyl is 0.86 μM which means the 4-methyl substituent is at least 20-fold more potent (see structures 22 and 23).

Celecoxib is compound 22; the 4-sulfamoylphenyl on the 1-pyrazol substituent is required for COX-2 inhibition and the 4-methyl on the 5-pyrazol system has low steric hindrance to maximize potency, while the 3-trifluoromethyl group provides superior selectivity and potency.[21] To explain the selectivity of celecoxib, it is necessary to analyze the free energy of binding difference between the drug molecule and COX-1 compared to COX-2 enzymes. The structural modifications highlight the importance of binding to residue 523 in the side binding pocket of the cyclooxygenase enzyme, which is an isoleucine in COX-1 and a valine in COX-2.[22] It appears that this mutation contributes to COX-2 selectivity by creating steric hindrance between the sulfonamide oxygen and the methyl group of Ile523 that effectively destabilizes the celecoxib-COX-1 complex.[22] Thus it is reasonable to expect COX-2 selective inhibitors to be more bulky than non-selective NSAIDs.

History[edit]

Two lawsuits arose over discovery of celecoxib. Daniel L. Simmons of Brigham Young University discovered the COX-2 enzyme,[23] and BYU entered into a collaboration with Monsanto to develop drugs to inhibit it. BYU ended up suing Pfizer for breach of contract.[24] A settlement was reached in April 2012 in which Pfizer agreed to pay $450 million.[25][26] Other important discoveries in COX-2 were made at University of Rochester, which patented the discoveries.[27] When the patent issued, the university sued Searle (later Pfizer) in a case called, University of Rochester v. G.D. Searle & Co., 358 F.3d 916 (Fed. Cir. 2004). The court ruled in favor of Searle in 2004, holding in essence that the university had claimed a method requiring, yet provided no written description of, a compound that could inhibit COX-2 and therefore the patent was invalid.[28][29]

Celecoxib was discovered and[30] developed by G. D. Searle & Company and was approved by the FDA on December 31, 1998.[31] It was co-promoted by Monsanto Company (parent company of Searle) and Pfizer under the brand name Celebrex. Monsanto merged with Pharmacia, from which the Medical Research Division was acquired by Pfizer, giving Pfizer ownership of Celebrex. The drug was at the core of a major patent dispute that was resolved in Searle's favor (later Pfizer) in 2004.[28][29] In University of Rochester v. G.D. Searle & Co., 358 F.3d 916 (Fed. Cir. 2004), the University of Rochester claimed that United States Pat. No. 6,048,850 (which claimed a method of inhibiting COX-2 in humans using a compound, without actually disclosing what that compound might be) covered drugs such as celecoxib. The court ruled in favor of Searle, holding in essence that the University had claimed a method requiring, yet provided no written description of, a compound that could inhibit COX-2 and therefore the patent was invalid.

After the withdrawal of rofecoxib (Vioxx) from the market in September 2004, Celebrex enjoyed a robust increase in sales. However, the results of the APC trial in December of that year raised concerns that Celebrex might carry risks similar to those of Vioxx, and Pfizer announced a moratorium on direct-to-consumer advertising of Celebrex soon afterwards. After a significant drop, sales of Celebrex have recovered, and reached $2 billion in 2006.[9] Pfizer resumed advertising Celebrex in magazines in 2006,[32] and resumed television advertising in April 2007 with an unorthodox, 2 12-minute advertisement which extensively discussed the adverse effects of Celebrex in comparison with other anti-inflammatory drugs. The ad drew criticism from the consumer advocacy group Public Citizen, which called the ad's comparisons misleading.[33] Pfizer responded to Public Citizen's concerns with assurances that they are truthfully advertising the risk and benefits of Celebrex as set forth by the FDA.[33]

In late 2007, Pfizer released another US television ad for Celebrex, which also discussed celecoxib's adverse effects in comparison with those of other anti-inflammatory drugs.

Availability[edit]

Pfizer markets celecoxib under the brand name Celebrex, and is available as oral capsules containing 50, 100, 200 or 400 mg of celecoxib.[34]

As of March 2013 Celecoxib is not available as a generic in the United States, because it is covered by unexpired Pfizer patents.[35] However, in other countries, including India and the Philippines, it is legally available as a generic under several brand names.[36]

Research[edit]

Cancer prevention[edit]

The role celecoxib might have in reducing the rates of certain cancers has been the subject of many studies. However, there is no current medical recommendation to use this drug for cancer reduction.

The use of celecoxib to reduce the risk of colorectal cancer has been investigated, but neither celecoxib nor any other drug is indicated for this use.[37] Twelve carcinogenesis studies in rats of mice showed celecoxib prevented intestinal cancer in those experimental settings.[38] Small-scale clinical trials in very high risk people (belonging to FAP families) also showed celecoxib can prevent polyp growth. Hence, large-scale randomized clinical trials were undertaken and results published by N. Arber and M. Bertagnolli in The New England Journal of Medicine, August 2006.[39] Results show a 33 to 45% polyp recurrence reduction in people taking 400–800 mg celecoxib each day. However, serious cardiovascular events were significantly more frequent in the celecoxib-treated groups (see above, cardiovascular toxicity). Aspirin shows a similar (and possibly larger) protective effect,[40][41][42] has demonstrated cardioprotective effects and is significantly cheaper, but there have been no head-to-head clinical trials comparing the two drugs.

Cancer treatment[edit]

Different from cancer prevention, cancer treatment is focused on the therapy of tumors that have already formed and have established themselves inside the patient. Many studies are ongoing to determine whether celecoxib might be useful for this latter condition.[43] However, during molecular studies in the laboratory, it became apparent that celecoxib could interact with other intracellular components besides its most famous target, cyclooxygenase 2 (COX-2). The discovery of these additional targets has generated much controversy, and the initial assumption that celecoxib reduces tumor growth primarily by the inhibition of COX-2 became contentious.[44]

Certainly, the inhibition of COX-2 is paramount for the anti-inflammatory and analgesic function of celecoxib. However, whether inhibition of COX-2 also plays a dominant role in this drug’s anticancer effects is unclear. For example, a recent study with malignant tumor cells showed celecoxib could inhibit the growth of these cells in vitro, but COX-2 played no role in this outcome; even more strikingly, the anticancer effects of celecoxib were also obtained with the use of cancer cell types that do not even contain COX-2.[45]

Additional support for the idea that other targets besides COX-2 are important for celecoxib's anticancer effects has come from studies with chemically modified versions of celecoxib. Several dozen analogs of celecoxib were generated with small alterations in their chemical structures.[46] Some of these analogs retained COX-2 inhibitory activity, whereas many others did not. However, when the ability of all these compounds to kill tumor cells in cell culture was investigated, the antitumor potency did not at all depend on whether or not the respective compound could inhibit COX-2, showing the inhibition of COX-2 was not required for the anticancer effects.[46][47] One of these compounds, 2,5-dimethyl-celecoxib, which entirely lacks the ability to inhibit COX-2, actually displayed stronger anticancer activity than celecoxib.[48]

Adhesion prevention[edit]

Celocoxib may prevent intra-abdominal adhesion formation. Adhesions are a common complication of surgery, especially abdominal surgery, and major cause of bowel obstruction and infertility. Publishing in 2005, researchers in Boston noticed a "dramatic" reduction in postsurgical adhesions in mice taking the drug celecoxib.[49] Multi-institutional trials in adult human patients are planned.[50] The initially suggested course of treatment is a mere seven to 10 days following surgery.[51]

References[edit]

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