Identification

Name
Valdecoxib
Accession Number
DB00580  (APRD00183, DB07576)
Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
Description

Valdecoxib was removed from the Canadian, U.S., and E.U. markets in 2005 due to concerns about possible increased risk of heart attack and stroke.

Structure
Thumb
Synonyms
Not Available
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
BextraTablet, film coated20 mg/1OralPhysicians Total Care, Inc.2002-04-302005-07-31Us
BextraTablet, film coated10 mg/1OralG.D. Searle LLC2006-02-06Not applicableUs
BextraTablet, film coated10 mg/1OralPhysicians Total Care, Inc.2001-11-162005-07-31Us
BextraTablet, film coated20 mg/1OralG.D. Searle LLC2006-02-06Not applicableUs
International/Other Brands
Bextra
Categories
UNII
2919279Q3W
CAS number
181695-72-7
Weight
Average: 314.359
Monoisotopic: 314.072513014
Chemical Formula
C16H14N2O3S
InChI Key
LNPDTQAFDNKSHK-UHFFFAOYSA-N
InChI
InChI=1S/C16H14N2O3S/c1-11-15(12-7-9-14(10-8-12)22(17,19)20)16(18-21-11)13-5-3-2-4-6-13/h2-10H,1H3,(H2,17,19,20)
IUPAC Name
4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)benzene-1-sulfonamide
SMILES
CC1=C(C(=NO1)C1=CC=CC=C1)C1=CC=C(C=C1)S(N)(=O)=O

Pharmacology

Indication

For the treatment of osteoarthritis and dysmenorrhoea

Pharmacodynamics

Valdecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is classified as a nonsteroidal anti-inflammatory drug (NSAID). Valdecoxib is used for its anti-inflammatory, analgesic, and antipyretic activities in the management of osteoarthritis (OA) and for the treatment of dysmenorrhea or acute pain. Unlike celecoxib, valdecoxib lacks a sulfonamide chain and does not require CYP450 enzymes for metabolism.

Mechanism of action

Both COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane. Valdecoxib selectively inhibits the cyclooxygenase-2 (COX-2) enzyme, important for the mediation of inflammation and pain. Unlike non-selective NSAIDs, valdecoxib does not inhibit platelet aggregation.

TargetActionsOrganism
AProstaglandin G/H synthase 2
inhibitor
Human
UCarbonic anhydrase 2
inhibitor
Human
UCarbonic anhydrase 3
inhibitor
Human
Absorption

Oral bioavailability is 83%.

Volume of distribution
  • 86 L
Protein binding

98%

Metabolism

Hepatic (involves CYP3A4 and 2C9)

Route of elimination

Valdecoxib is eliminated predominantly via hepatic metabolism with less than 5% of the dose excreted unchanged in the urine and feces. About 70% of the dose is excreted in the urine as metabolites, and about 20% as valdecoxib N-glucuronide.

Half life

8-11 hours

Clearance
  • oral cl=6 L/h
  • 6 – 7 L/h [In patients undergoing hemodialysis]
  • 6 – 7 L/h [healthy elderly subjects]
Toxicity

Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare.

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Valdecoxib Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of bleeding and hemorrhage can be increased when Valdecoxib is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding and hemorrhage can be increased when Valdecoxib is combined with (S)-Warfarin.
16-BromoepiandrosteroneThe metabolism of 16-Bromoepiandrosterone can be decreased when combined with Valdecoxib.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Valdecoxib.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Valdecoxib.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Valdecoxib.
6-Deoxyerythronolide BThe metabolism of Valdecoxib can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Valdecoxib.
AbacavirValdecoxib may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbciximabThe risk or severity of bleeding and hemorrhage can be increased when Valdecoxib is combined with Abciximab.
Food Interactions
Not Available

References

Synthesis Reference

Eswaraiah Sajja, Anumula Reddy, Aalla Sampath, Gilla Goverdhan, "Process for preparing crystalline form A of valdecoxib." U.S. Patent US20050272787, issued December 08, 2005.

US20050272787
General References
Not Available
External Links
Human Metabolome Database
HMDB0005033
PubChem Compound
119607
PubChem Substance
46506229
ChemSpider
106796
BindingDB
13063
ChEBI
63634
ChEMBL
CHEMBL865
Therapeutic Targets Database
DAP001541
PharmGKB
PA10226
HET
COX
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Valdecoxib
ATC Codes
M01AH03 — Valdecoxib
PDB Entries
2aw1
FDA label
Download (82.8 KB)
MSDS
Download (70.6 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentKnee Osteoarthritis (Knee OA)1
2CompletedTreatmentPain NOS1
2, 3TerminatedPreventionERCP / Pancreatitis1
3CompletedTreatmentHallux Valgus / Pain NOS1
3CompletedTreatmentKnee / Osteoarthritis (OA)1
3CompletedTreatmentLaparoscopic Cholecystectomy / Pain NOS1
3CompletedTreatmentOsteoarthritis (OA)1
3CompletedTreatmentPain NOS2
3CompletedTreatmentPain, Post-Surgical1
3CompletedTreatmentPharyngitis1
3CompletedTreatmentPostoperative pain2
3TerminatedTreatmentPain NOS1
4CompletedPreventionHyperalgesia / Pain NOS1
4CompletedTreatmentDysmenorrhea1
4CompletedTreatmentLow Back Pain (LBP)1
4CompletedTreatmentNeurosurgery / Pain NOS1
4CompletedTreatmentPain NOS / Sprains / Sprains and Strains1
4CompletedTreatmentPostoperative pain1
4CompletedTreatmentRheumatoid Arthritis1
4CompletedTreatmentRupture of Anterior Cruciate Ligament1
4TerminatedTreatmentPain, Acute1
4TerminatedTreatmentPost Surgical Pain1
Not AvailableCompletedBasic SciencePlatelet Aggregation1
Not AvailableCompletedSupportive CarePain NOS / Unspecified Adult Solid Tumor, Protocol Specific1
Not AvailableCompletedTreatmentPostoperative pain1

Pharmacoeconomics

Manufacturers
  • Gd searle llc
Packagers
  • Cardinal Health
  • GD Searle LLC
  • Murfreesboro Pharmaceutical Nursing Supply
  • PD-Rx Pharmaceuticals Inc.
  • Pfizer Inc.
  • Physicians Total Care Inc.
Dosage forms
FormRouteStrength
Tablet, film coatedOral10 mg/1
Tablet, film coatedOral20 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7135489No1997-08-122017-08-12Us
US5633272No1995-02-132015-02-13Us
CA2212836No2003-08-122016-02-12Canada

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP3.2Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0348 mg/mLALOGPS
logP3.32ALOGPS
logP2.82ChemAxon
logS-4ALOGPS
pKa (Strongest Acidic)10.06ChemAxon
pKa (Strongest Basic)0.42ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area86.19 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity84.71 m3·mol-1ChemAxon
Polarizability31.76 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9386
Caco-2 permeable+0.5
P-glycoprotein substrateNon-substrate0.8864
P-glycoprotein inhibitor INon-inhibitor0.8772
P-glycoprotein inhibitor IINon-inhibitor0.9157
Renal organic cation transporterNon-inhibitor0.8576
CYP450 2C9 substrateNon-substrate0.7356
CYP450 2D6 substrateSubstrate0.8918
CYP450 3A4 substrateNon-substrate0.6501
CYP450 1A2 substrateNon-inhibitor0.5759
CYP450 2C9 inhibitorInhibitor0.5385
CYP450 2D6 inhibitorNon-inhibitor0.8875
CYP450 2C19 inhibitorInhibitor0.5958
CYP450 3A4 inhibitorNon-inhibitor0.8652
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.7649
Ames testNon AMES toxic0.8277
CarcinogenicityNon-carcinogens0.7399
BiodegradationNot ready biodegradable0.9948
Rat acute toxicity2.0680 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9708
hERG inhibition (predictor II)Non-inhibitor0.8652
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-014i-0439000000-984ffa23e74fb8949b56
MS/MS Spectrum - , positiveLC-MS/MSsplash10-014i-0439000000-8928b5e8f850f43f1430
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0089-2930000000-dac70ddadd2ffd150b22

Taxonomy

Description
This compound belongs to the class of organic compounds known as benzenesulfonamides. These are organic compounds containing a sulfonamide group that is S-linked to a benzene ring.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzenesulfonamides
Direct Parent
Benzenesulfonamides
Alternative Parents
Benzenesulfonyl compounds / Organosulfonamides / Isoxazoles / Heteroaromatic compounds / Aminosulfonyl compounds / Oxacyclic compounds / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds / Organonitrogen compounds
show 2 more
Substituents
Benzenesulfonamide / Benzenesulfonyl group / Organosulfonic acid amide / Azole / Isoxazole / Organic sulfonic acid or derivatives / Organosulfonic acid or derivatives / Heteroaromatic compound / Aminosulfonyl compound / Sulfonyl
show 12 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
sulfonamide, isoxazoles (CHEBI:63634)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Prostaglandin-endoperoxide synthase activity
Specific Function
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and...
Gene Name
PTGS2
Uniprot ID
P35354
Uniprot Name
Prostaglandin G/H synthase 2
Molecular Weight
68995.625 Da
References
  1. Talley JJ, Brown DL, Carter JS, Graneto MJ, Koboldt CM, Masferrer JL, Perkins WE, Rogers RS, Shaffer AF, Zhang YY, Zweifel BS, Seibert K: 4-[5-Methyl-3-phenylisoxazol-4-yl]- benzenesulfonamide, valdecoxib: a potent and selective inhibitor of COX-2. J Med Chem. 2000 Mar 9;43(5):775-7. [PubMed:10715145]
  2. Jain KK: Evaluation of intravenous parecoxib for the relief of acute post-surgical pain. Expert Opin Investig Drugs. 2000 Nov;9(11):2717-23. [PubMed:11060833]
  3. Yuan JJ, Yang DC, Zhang JY, Bible R Jr, Karim A, Findlay JW: Disposition of a specific cyclooxygenase-2 inhibitor, valdecoxib, in human. Drug Metab Dispos. 2002 Sep;30(9):1013-21. [PubMed:12167567]
  4. Tacconelli S, Capone ML, Sciulli MG, Ricciotti E, Patrignani P: The biochemical selectivity of novel COX-2 inhibitors in whole blood assays of COX-isozyme activity. Curr Med Res Opin. 2002;18(8):503-11. [PubMed:12564662]
  5. Hood WF, Gierse JK, Isakson PC, Kiefer JR, Kurumbail RG, Seibert K, Monahan JB: Characterization of celecoxib and valdecoxib binding to cyclooxygenase. Mol Pharmacol. 2003 Apr;63(4):870-7. [PubMed:12644588]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  7. Gierse JK, Zhang Y, Hood WF, Walker MC, Trigg JS, Maziasz TJ, Koboldt CM, Muhammad JL, Zweifel BS, Masferrer JL, Isakson PC, Seibert K: Valdecoxib: assessment of cyclooxygenase-2 potency and selectivity. J Pharmacol Exp Ther. 2005 Mar;312(3):1206-12. Epub 2004 Oct 19. [PubMed:15494548]
Details
2. Carbonic anhydrase 2
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion in...
Gene Name
CA2
Uniprot ID
P00918
Uniprot Name
Carbonic anhydrase 2
Molecular Weight
29245.895 Da
References
  1. Nishimori I, Minakuchi T, Onishi S, Vullo D, Cecchi A, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors: cloning, characterization, and inhibition studies of the cytosolic isozyme III with sulfonamides. Bioorg Med Chem. 2007 Dec 1;15(23):7229-36. Epub 2007 Aug 25. [PubMed:17826101]
Details
3. Carbonic anhydrase 3
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Reversible hydration of carbon dioxide.
Gene Name
CA3
Uniprot ID
P07451
Uniprot Name
Carbonic anhydrase 3
Molecular Weight
29557.215 Da
References
  1. Nishimori I, Minakuchi T, Onishi S, Vullo D, Cecchi A, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors: cloning, characterization, and inhibition studies of the cytosolic isozyme III with sulfonamides. Bioorg Med Chem. 2007 Dec 1;15(23):7229-36. Epub 2007 Aug 25. [PubMed:17826101]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Agundez JA, Garcia-Martin E, Martinez C: Genetically based impairment in CYP2C8- and CYP2C9-dependent NSAID metabolism as a risk factor for gastrointestinal bleeding: is a combination of pharmacogenomics and metabolomics required to improve personalized medicine? Expert Opin Drug Metab Toxicol. 2009 Jun;5(6):607-20. doi: 10.1517/17425250902970998 . [PubMed:19422321]
  2. Valdexocib FDA label [File]
  3. EMA public statement: Valdecoxib [File]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks trans...
Gene Name
UGT1A9
Uniprot ID
O60656
Uniprot Name
UDP-glucuronosyltransferase 1-9
Molecular Weight
59940.495 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]

Drug created on June 13, 2005 07:24 / Updated on October 21, 2018 20:24