Identification

Name
Lumiracoxib
Accession Number
DB01283
Type
Small Molecule
Groups
Approved, 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
  • Lumiracoxibum
External IDs
COX 189 / COX-189 / COX189
International/Other Brands
Prexige (Novartis)
Categories
UNII
V91T9204HU
CAS number
220991-20-8
Weight
Average: 293.721
Monoisotopic: 293.061884577
Chemical Formula
C15H13ClFNO2
InChI Key
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

Pharmacology

Indication

For the acute and chronic treatment of the signs and symptoms of osteoarthritis of the knee in adults.

Pharmacodynamics

Lumiracoxib 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 action

The 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.

TargetActionsOrganism
AProstaglandin G/H synthase 2
inhibitor
Human
AProstaglandin G/H synthase 1
inhibitor
Human
Absorption

Rapidly absorbed following oral administration, with an absolute oral bioavailablity of 74%.

Volume of distribution
Not Available
Protein binding

Highly 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.

Route of elimination
Not Available
Half life

Terminal half-life is approximately 4 hours.

Clearance
Not Available
Toxicity

Single 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
PathwayCategory
Lumiracoxib Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(4R)-limoneneThe risk or severity of adverse effects can be increased when (4R)-limonene is combined with Lumiracoxib.
16-BromoepiandrosteroneThe risk or severity of adverse effects can be increased when Lumiracoxib is combined with 16-Bromoepiandrosterone.
19-norandrostenedioneThe risk or severity of adverse effects can be increased when Lumiracoxib is combined with 19-norandrostenedione.
5-androstenedioneThe risk or severity of adverse effects can be increased when Lumiracoxib is combined with 5-androstenedione.
AbciximabThe risk or severity of bleeding and hemorrhage can be increased when Lumiracoxib is combined with Abciximab.
AbirateroneThe serum concentration of Lumiracoxib can be increased when it is combined with Abiraterone.
AcebutololLumiracoxib may decrease the antihypertensive activities of Acebutolol.
AceclofenacThe risk or severity of adverse effects can be increased when Lumiracoxib is combined with Aceclofenac.
AcemetacinThe risk or severity of adverse effects can be increased when Lumiracoxib is combined with Acemetacin.
AcenocoumarolThe risk or severity of bleeding and hemorrhage can be increased when Lumiracoxib is combined with Acenocoumarol.
Food Interactions
  • Take with or without food. Food has no effect on the absorption of the product.

References

General References
Not Available
External Links
Human Metabolome Database
HMDB0015403
KEGG Drug
D03714
PubChem Compound
151166
PubChem Substance
46506378
ChemSpider
133236
BindingDB
50207446
ChEBI
73044
ChEMBL
CHEMBL404108
Therapeutic Targets Database
DAP000970
PharmGKB
PA164769031
HET
LUR
Wikipedia
Lumiracoxib
ATC Codes
M01AH06 — Lumiracoxib
PDB Entries
4iiz / 4ik6 / 4oty / 4rrw / 4rrx / 4rrz

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2TerminatedTreatmentArthralgia/joint pain / Chronic Renal Failure (CRF)1
3CompletedTreatmentKnee Osteoarthritis (Knee OA)2
3CompletedTreatmentOsteoarthritis (OA)4
3CompletedTreatmentOsteoarthritis (OA) / Rheumatoid Arthritis1
3CompletedTreatmentOsteoarthritis, Hip1
4CompletedTreatmentAcute Gouty Arthritis1
4CompletedTreatmentControlled Hypertension / Osteoarthritis (OA)1
4CompletedTreatmentHealthy Volunteers1
4CompletedTreatmentOsteoarthritis With Controlled Hypertension1
4CompletedTreatmentPain2
4CompletedTreatmentPainful musculoskeletal conditions1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
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 RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

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

Taxonomy

Description
This compound belongs to the class of organic compounds known as aminotoluenes. These are organic aromatic compounds containing a benzene that carries a single methyl group and one amino group.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Toluenes
Direct Parent
Aminotoluenes
Alternative Parents
Aniline and substituted anilines / Fluorobenzenes / Chlorobenzenes / Aryl fluorides / Aryl chlorides / Amino acids / Secondary amines / Monocarboxylic acids and derivatives / Carboxylic acids / Organopnictogen compounds
show 5 more
Substituents
Aminotoluene / Aniline or substituted anilines / Chlorobenzene / Fluorobenzene / Halobenzene / Aryl chloride / Aryl fluoride / Aryl halide / Amino acid or derivatives / Amino acid
show 17 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
organofluorine compound, monocarboxylic acid, organochlorine compound, secondary amino compound, amino acid (CHEBI:73044)

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. 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 gas...
Gene Name
PTGS1
Uniprot ID
P23219
Uniprot Name
Prostaglandin G/H synthase 1
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 un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
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 im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
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 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]
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 un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
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]
  2. Rordorf CM, Choi L, Marshall P, Mangold JB: Clinical pharmacology of lumiracoxib: a selective cyclo-oxygenase-2 inhibitor. Clin Pharmacokinet. 2005;44(12):1247-66. doi: 10.2165/00003088-200544120-00004. [PubMed:16372823]

Drug created on May 17, 2007 10:57 / Updated on October 01, 2018 13:02