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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GroupsInvestigational, Withdrawn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
SaltsNot Available
Brand names
NameCompany
BextraNot Available
Brand mixturesNot Available
Categories
CAS number181695-72-7
WeightAverage: 314.359
Monoisotopic: 314.072513014
Chemical FormulaC16H14N2O3S
InChI KeyLNPDTQAFDNKSHK-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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassPhenylpropanoids and Polyketides
ClassStilbenes
SubclassNot Available
Direct parentStilbenes
Alternative parentsBenzenesulfonamides; Sulfonyls; Sulfonamides; Isoxazoles; Polyamines
Substituentsbenzenesulfonamide; benzene; sulfonic acid derivative; sulfonyl; azole; isoxazole; sulfonamide; polyamine; organonitrogen compound
Classification descriptionThis compound belongs to the stilbenes. These are organic compounds containing a 1,2-diphenylethylene moiety. Stilbenes (C6-C2-C6 ) are derived from the common phenylpropene (C6-C3) skeleton building block. The introduction of one or more hydroxyl groups to a phenyl ring lead to stilbenoids.
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.
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
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 1.0
Blood Brain Barrier + 0.9386
Caco-2 permeable + 0.5
P-glycoprotein substrate Non-substrate 0.8864
P-glycoprotein inhibitor I Non-inhibitor 0.8772
P-glycoprotein inhibitor II Non-inhibitor 0.9157
Renal organic cation transporter Non-inhibitor 0.8576
CYP450 2C9 substrate Non-substrate 0.7356
CYP450 2D6 substrate Substrate 0.8918
CYP450 3A4 substrate Non-substrate 0.6501
CYP450 1A2 substrate Non-inhibitor 0.5759
CYP450 2C9 substrate Inhibitor 0.5385
CYP450 2D6 substrate Non-inhibitor 0.8875
CYP450 2C19 substrate Inhibitor 0.5958
CYP450 3A4 substrate Non-inhibitor 0.8652
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.7649
Ames test Non AMES toxic 0.8277
Carcinogenicity Non-carcinogens 0.7399
Biodegradation Not ready biodegradable 0.9948
Rat acute toxicity 2.0680 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9708
hERG inhibition (predictor II) Non-inhibitor 0.8652
Pharmacoeconomics
Manufacturers
  • Gd searle llc
Packagers
Dosage forms
FormRouteStrength
TabletOral
PricesNot Available
Patents
CountryPatent NumberApprovedExpires (estimated)
United States71354891997-08-122017-08-12
United States56332721995-02-132015-02-13
Canada22128362003-08-122016-02-12
Properties
Statesolid
Experimental Properties
PropertyValueSource
logP3.2Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0348ALOGPS
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
Spectra
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 ReferenceNot Available
External Links
ResourceLink
PubChem Compound119607
PubChem Substance46506229
ChemSpider106796
BindingDB13063
Therapeutic Targets DatabaseDAP001541
PharmGKBPA10226
HETCOX
Drug Product Database2246622
RxListhttp://www.rxlist.com/cgi/generic/bextra.htm
Drugs.comhttp://www.drugs.com/mtm/valdecoxib.html
WikipediaValdecoxib
ATC CodesM01AH03
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelshow(82.8 KB)
MSDSshow(70.6 KB)
Interactions
Drug Interactions
Drug
FluconazoleFluconazole may increase the effect and toxicity of valdecoxib.
KetoconazoleKetoconazole may increase the effect and toxicity of valdecoxib.
LithiumThe COX-2 inhibitor increases serum levels of lithium
Food InteractionsNot Available

Targets

1. Prostaglandin G/H synthase 2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Prostaglandin G/H synthase 2 P35354 Details

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
  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
  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
  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
  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
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  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

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

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
  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. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

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
  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. Epub 2009 Nov 24. Pubmed

3. Prostaglandin G/H synthase 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Prostaglandin G/H synthase 1 P23219 Details

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

4. UDP-glucuronosyltransferase 1-9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-9 O60656 Details

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

5. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 Details

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. Epub 2009 Nov 24. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:11