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Identification
NameValdecoxib
Accession NumberDB00580  (APRD00183, DB07576)
TypeSmall Molecule
GroupsInvestigational, Withdrawn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
SynonymsNot Available
External Identifiers Not Available
Prescription ProductsNot Available
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NameCompany
BextraNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII2919279Q3W
CAS number181695-72-7
WeightAverage: 314.359
Monoisotopic: 314.072513014
Chemical FormulaC16H14N2O3S
InChI KeyInChIKey=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
Taxonomy
DescriptionThis 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.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassBenzenesulfonamides
Direct ParentBenzenesulfonamides
Alternative Parents
Substituents
  • Benzenesulfonamide
  • Heteroaromatic compound
  • Aminosulfonyl compound
  • Sulfonyl
  • Sulfonic acid derivative
  • Sulfonamide
  • Oxazole
  • Isoxazole
  • Azole
  • Oxacycle
  • Azacycle
  • Organoheterocyclic compound
  • Hydrocarbon derivative
  • Organosulfur compound
  • Organooxygen compound
  • Organonitrogen compound
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment of osteoarthritis and dysmenorrhoea
PharmacodynamicsValdecoxib, 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 actionBoth 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.
Related Articles
AbsorptionOral bioavailability is 83%.
Volume of distribution
  • 86 L
Protein binding98%
Metabolism

Hepatic (involves CYP3A4 and 2C9)

SubstrateEnzymesProduct
Valdecoxib
Valdecoxib N-glucuronideDetails
Valdecoxib
Not Available
Valdecoxib metabolite M2Details
Valdecoxib metabolite M2
Valdecoxib metabolite M2 glucuronideDetails
Valdecoxib metabolite M2
Not Available
Valdecoxib metabolite M7Details
Valdecoxib metabolite M7
Not Available
Valdecoxib metabolite M8Details
Valdecoxib metabolite M2
Not Available
Valdecoxib metabolite M5Details
Valdecoxib metabolite M5
Valdecoxib metabolite M5 glucuronideDetails
Valdecoxib
Valdecoxib metabolite M1Details
Valdecoxib metabolite M1
Valdecoxib metabolite M1 glucuronideDetails
Valdecoxib metabolite M1
Not Available
Valdecoxib metabolite M5Details
Valdecoxib metabolite M1
Not Available
Valdecoxib metabolite M4Details
Valdecoxib metabolite M1
Not Available
Valdecoxib metabolite M3Details
Valdecoxib metabolite M3
Valdecoxib metabolite M3 glucuronideDetails
Valdecoxib
Valdecoxib metabolite M9Details
Valdecoxib metabolite M9
Valdecoxib metabolite M3Details
Valdecoxib metabolite M9
Valdecoxib metabolite M9 glucuronideDetails
Route of eliminationValdecoxib 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 life8-11 hours
Clearance
  • oral cl=6 L/h
  • 6 – 7 L/h [In patients undergoing hemodialysis]
  • 6 – 7 L/h [healthy elderly subjects]
ToxicitySymptoms 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
PathwayCategorySMPDB ID
Valdecoxib Action PathwayDrug actionSMP00116
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 )
Pharmacoeconomics
Manufacturers
  • Gd searle llc
Packagers
Dosage formsNot Available
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2212836 No2003-08-122016-02-12Canada
US5633272 No1995-02-132015-02-13Us
US7135489 No1997-08-122017-08-12Us
Properties
StateSolid
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 RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot 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 ReferencesNot Available
External Links
ATC CodesM01AH03
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (82.8 KB)
MSDSDownload (70.6 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

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 brain, and in pathological conditions, such as in cancer. PTGS2 is responsible for production of inflammatory prostaglandins. Up-regulation of PTGS2 is also associated with increased cell adhesion, p...
Gene Name:
PTGS2
Uniprot ID:
P35354
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 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
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 unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenyto...
Gene Name:
CYP2C9
Uniprot ID:
P11712
Molecular Weight:
55627.365 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
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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
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
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 transferase activity but acts as a negative regulator of isoform 1.
Gene Name:
UGT1A9
Uniprot ID:
O60656
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 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Steroid hydroxylase activity
Specific Function:
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine.
Gene Name:
CYP2C19
Uniprot ID:
P33261
Molecular Weight:
55930.545 Da
References
  1. 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 ]
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Drug created on June 13, 2005 07:24 / Updated on October 21, 2015 10:45