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Identification
NameLumiracoxib
Accession NumberDB01283
TypeSmall Molecule
GroupsApproved, Investigational
Description

Lumiracoxib is a COX-2 selective inhibitor non-steroidal anti-inflammatory drug. On August 11, 2007, Australia’s Therapeutic Goods Administration (TGA, the Australian equivalent of the FDA) cancelled the registration of lumiracoxib in Australia due to concerns that it may cause liver failure. New Zealand and Canada have also followed suit in recalling the drug.

Structure
Thumb
Synonyms
2-((2-chloro-6-Fluorophenyl)amino)-5-methylbenzeneacetic acid
COX 189
COX-189
COX189
Lumiracoxibum
Prexige
External Identifiers Not Available
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
PrexigeNovartis
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIV91T9204HU
CAS number220991-20-8
WeightAverage: 293.721
Monoisotopic: 293.061884577
Chemical FormulaC15H13ClFNO2
InChI KeyInChIKey=KHPKQFYUPIUARC-UHFFFAOYSA-N
InChI
InChI=1S/C15H13ClFNO2/c1-9-5-6-13(10(7-9)8-14(19)20)18-15-11(16)3-2-4-12(15)17/h2-7,18H,8H2,1H3,(H,19,20)
IUPAC Name
2-{2-[(2-chloro-6-fluorophenyl)amino]-5-methylphenyl}acetic acid
SMILES
CC1=CC=C(NC2=C(Cl)C=CC=C2F)C(CC(O)=O)=C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as phenylacetic acid derivatives. These are compounds containing a phenylacetic acid moiety, which consists of a phenyl group substituted at the second position by an acetic acid.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassPhenylacetic acid derivatives
Direct ParentPhenylacetic acid derivatives
Alternative Parents
Substituents
  • Phenylacetate
  • Aminotoluene
  • Substituted aniline
  • Toluene
  • Halobenzene
  • Fluorobenzene
  • Chlorobenzene
  • Aniline
  • Aryl halide
  • Aryl fluoride
  • Aryl chloride
  • Secondary amine
  • Monocarboxylic acid or derivatives
  • Carboxylic acid
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organochloride
  • Organohalogen compound
  • Carbonyl group
  • Amine
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
Pharmacology
IndicationFor the acute and chronic treatment of the signs and symptoms of osteoarthritis of the knee in adults.
PharmacodynamicsLumiracoxib has a different structure from the standard COX-2 inhibitors (e.g. celecoxib). It more closely resembles the structure of diclofenac (one chlorine substituted by fluorine, the phenylacetic acid has another methyl group in meta position), making it a member of the arylalkanoic acid family of NSAIDs. It binds to a different site on the COX-2 receptor than the standard COX-2 inhibitors. It displays extremely high COX-2 selectivity.
Mechanism of actionThe mechanism of action of lumiracoxib is due to inhibition of prostaglandin synthesis via inhibition of cyclooygenase-2 (COX-2). Lumiracoxib does not inhibit COX-1 at therapeutic concentrations.
Related Articles
AbsorptionRapidly absorbed following oral administration, with an absolute oral bioavailablity of 74%.
Volume of distributionNot Available
Protein bindingHighly bound to plasma proteins (>= 98%).
Metabolism

Hepatic oxidation and hydroxylation via CYP2C9. Three major metabolites have been identified in plasma: 4'-hydroxy-lumiracoxib, 5-carboxy-lumiracoxib, and 4'-hydroxy-5-carboxy-lumiracoxib.

SubstrateEnzymesProduct
Lumiracoxib
Lumiracoxib metabolite M21Details
Lumiracoxib metabolite M21
Not Available
5-Carboxylumiracoxib (M11)Details
5-Carboxylumiracoxib (M11)
Not Available
Lumiracoxib metabolite M15Details
Lumiracoxib metabolite M15
Lumiracoxib metabolite M16/17Details
5-Carboxylumiracoxib (M11)
5-Carboxylumiracoxib glucuronide (M3)Details
Lumiracoxib
Lumiracoxib glucuronide (M24)Details
Lumiracoxib
4'-hydroxylumiracoxib (M23)Details
4'-hydroxylumiracoxib (M23)
4'-Carboxylumiracoxib glucuronide (M22)Details
4'-hydroxylumiracoxib (M23)
Not Available
Lumiracoxib metabolite M25Details
Lumiracoxib metabolite M25
Lumiracoxib metabolite M25 glucuronide (M20)Details
4'-hydroxylumiracoxib (M23)
Not Available
Lumiracoxib metabolite M9Details
Lumiracoxib metabolite M9
Not Available
4'-Hydroxy-5-carboxylumiracoxib (M5)Details
4'-Hydroxy-5-carboxylumiracoxib (M5)
Lumiracoxib metabolite M2Details
4'-Hydroxy-5-carboxylumiracoxib (M5)
Not Available
Lumiracoxib metabolite M8Details
Lumiracoxib metabolite M8
Not Available
Lumiracoxib metabolite M4/M6Details
Lumiracoxib metabolite M8
Lumiracoxib metabolite M10Details
Lumiracoxib metabolite M8
Not Available
Hydroxylumiracoxib metabolite M8 (M12)Details
Hydroxylumiracoxib metabolite M8 (M12)
Lumiracoxib metabolite M12 glucuronide (M13)Details
5-Carboxylumiracoxib (M11)
Not Available
4'-Hydroxy-5-carboxylumiracoxib (M5)Details
Lumiracoxib metabolite M21
Not Available
Lumiracoxib metabolite M9Details
Lumiracoxib metabolite M15
Not Available
Lumiracoxib metabolite M8Details
Route of eliminationNot Available
Half lifeTerminal half-life is approximately 4 hours.
ClearanceNot Available
ToxicitySingle oral doses in mice and rats resulted in mortality and/or moribundity at doses of 600 mg/kg and 500 mg/kg, respectively. Single intraperitoneal doses in mice and rats results in mortality/moribundity at 750 mg/kg and 1000 mg/kg, respectively. The maximum non-lethal single oral and intraperitoneal dose in mouse was 300 mg/kg and 250 mg/kg, respectively. In the rat it was 150 mg/kg and 250 mg/kg, respectively.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Lumiracoxib Action PathwayDrug actionSMP00699
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9825
Blood Brain Barrier+0.9715
Caco-2 permeable+0.818
P-glycoprotein substrateNon-substrate0.7336
P-glycoprotein inhibitor INon-inhibitor0.7134
P-glycoprotein inhibitor IINon-inhibitor0.9389
Renal organic cation transporterNon-inhibitor0.916
CYP450 2C9 substrateNon-substrate0.7247
CYP450 2D6 substrateNon-substrate0.8639
CYP450 3A4 substrateNon-substrate0.5964
CYP450 1A2 substrateInhibitor0.5208
CYP450 2C9 inhibitorInhibitor0.6844
CYP450 2D6 inhibitorNon-inhibitor0.8163
CYP450 2C19 inhibitorNon-inhibitor0.8576
CYP450 3A4 inhibitorNon-inhibitor0.8063
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6222
Ames testNon AMES toxic0.8453
CarcinogenicityNon-carcinogens0.6326
BiodegradationNot ready biodegradable0.9954
Rat acute toxicity3.5160 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9512
hERG inhibition (predictor II)Non-inhibitor0.7169
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
logP3.9Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00549 mg/mLALOGPS
logP4.56ALOGPS
logP4.31ChemAxon
logS-4.7ALOGPS
pKa (Strongest Acidic)4.11ChemAxon
pKa (Strongest Basic)-1.9ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area49.33 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity75.91 m3·mol-1ChemAxon
Polarizability28.53 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
References
Synthesis ReferenceNot Available
General ReferencesNot Available
External Links
ATC CodesM01AH06
AHFS Codes
  • 28:08.04.08
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
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. Capone ML, Tacconelli S, Sciulli MG, Patrignani P: Clinical pharmacology of selective COX-2 inhibitors. Int J Immunopathol Pharmacol. 2003 May-Aug;16(2 Suppl):49-58. [PubMed:14552704 ]
  2. Tacconelli S, Capone ML, Patrignani P: Clinical pharmacology of novel selective COX-2 inhibitors. Curr Pharm Des. 2004;10(6):589-601. [PubMed:14965322 ]
  3. Atherton C, Jones J, McKaig B, Bebb J, Cunliffe R, Burdsall J, Brough J, Stevenson D, Bonner J, Rordorf C, Scott G, Branson J, Hawkey CJ: Pharmacology and gastrointestinal safety of lumiracoxib, a novel cyclooxygenase-2 selective inhibitor: An integrated study. Clin Gastroenterol Hepatol. 2004 Feb;2(2):113-20. [PubMed:15017615 ]
  4. Kalbag J, Yeh CM, Milosavljev S, Lasseter K, Oberstein S, Rordorf C: No influence of moderate hepatic impairment on the pharmacokinetics of lumiracoxib, an oral COX-2 selective inhibitor. Pharmacol Res. 2004 Aug;50(2):181-6. [PubMed:15177307 ]
  5. Esser R, Berry C, Du Z, Dawson J, Fox A, Fujimoto RA, Haston W, Kimble EF, Koehler J, Peppard J, Quadros E, Quintavalla J, Toscano K, Urban L, van Duzer J, Zhang X, Zhou S, Marshall PJ: Preclinical pharmacology of lumiracoxib: a novel selective inhibitor of cyclooxygenase-2. Br J Pharmacol. 2005 Feb;144(4):538-50. [PubMed:15655513 ]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
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. Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gastric epithelial cells, it is a key step in the generation of prostaglandins, such as prostaglandin E2 (PGE2), which plays an important role in cytoprotection. In platelets, it is involved in the gener...
Gene Name:
PTGS1
Uniprot ID:
P23219
Molecular Weight:
68685.82 Da
References
  1. Capone ML, Tacconelli S, Sciulli MG, Patrignani P: Clinical pharmacology of selective COX-2 inhibitors. Int J Immunopathol Pharmacol. 2003 May-Aug;16(2 Suppl):49-58. [PubMed:14552704 ]
  2. Esser R, Berry C, Du Z, Dawson J, Fox A, Fujimoto RA, Haston W, Kimble EF, Koehler J, Peppard J, Quadros E, Quintavalla J, Toscano K, Urban L, van Duzer J, Zhang X, Zhou S, Marshall PJ: Preclinical pharmacology of lumiracoxib: a novel selective inhibitor of cyclooxygenase-2. Br J Pharmacol. 2005 Feb;144(4):538-50. [PubMed:15655513 ]
  3. Jermany J, Branson J, Schmouder R, Guillaume M, Rordorf C: Lumiracoxib does not affect the ex vivo antiplatelet aggregation activity of low-dose aspirin in healthy subjects. J Clin Pharmacol. 2005 Oct;45(10):1172-8. [PubMed:16172182 ]
  4. Warner TD, Vojnovic I, Bishop-Bailey D, Mitchell JA: Influence of plasma protein on the potencies of inhibitors of cyclooxygenase-1 and -2. FASEB J. 2006 Mar;20(3):542-4. Epub 2006 Jan 10. [PubMed:16403783 ]
  5. Blobaum AL, Marnett LJ: Molecular determinants for the selective inhibition of cyclooxygenase-2 by lumiracoxib. J Biol Chem. 2007 Jun 1;282(22):16379-90. Epub 2007 Apr 12. [PubMed:17434872 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
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:
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. 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
substrate
General Function:
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N...
Gene Name:
CYP1A2
Uniprot ID:
P05177
Molecular Weight:
58293.76 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 May 17, 2007 10:57 / Updated on August 17, 2016 12:23