Identification

Name
Febuxostat
Accession Number
DB04854  (DB03786)
Type
Small Molecule
Groups
Approved
Description

Febuxostat is a xanathine oxidase (XO) inhibitor indicated in patients with gout suffering from hyperuricemia and is used in its chronic management. Febuxostat is not recommended for the treatment of asymptomatic hyperuricemia. Febuxostat is marketed under the trade name Uloric by Takeda Pharmaceuticals America, Inc., and was approved by the FDA in February 2009.

Structure
Thumb
Synonyms
  • 2-(3-cyano-4-isobutoxyphenyl)-4-methyl- 1,3-thiazole-5-carboxylic acid
  • Fébuxostat
  • Febuxostat
  • Febuxostatum
External IDs
TEI-6720 / TMX-67 / UNII-101V0R1N2E
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AdenuricTablet, film coated120 mgOralMenarini International Operations Luxembourg S.A. (Miol)2008-04-21Not applicableEu
AdenuricTablet, film coated80 mgOralMenarini International Operations Luxembourg S.A. (Miol)2008-04-21Not applicableEu
AdenuricTablet, film coated80 mgOralMenarini International Operations Luxembourg S.A. (Miol)2008-04-21Not applicableEu
AdenuricTablet, film coated120 mgOralMenarini International Operations Luxembourg S.A. (Miol)2008-04-21Not applicableEu
AdenuricTablet, film coated80 mgOralMenarini International Operations Luxembourg S.A. (Miol)2008-04-21Not applicableEu
AdenuricTablet, film coated80 mgOralMenarini International Operations Luxembourg S.A. (Miol)2008-04-21Not applicableEu
AdenuricTablet, film coated80 mgOralMenarini International Operations Luxembourg S.A. (Miol)2008-04-21Not applicableEu
AdenuricTablet, film coated120 mgOralMenarini International Operations Luxembourg S.A. (Miol)2008-04-21Not applicableEu
AdenuricTablet, film coated120 mgOralMenarini International Operations Luxembourg S.A. (Miol)2008-04-21Not applicableEu
AdenuricTablet, film coated120 mgOralMenarini International Operations Luxembourg S.A. (Miol)2008-04-21Not applicableEu
International/Other Brands
Adenuric (A. Menarini) / Atenurix (Ajanta Pharma Phil) / Barif (Square) / Feburic (Teijin Pharma)
Categories
UNII
101V0R1N2E
CAS number
144060-53-7
Weight
Average: 316.375
Monoisotopic: 316.088163078
Chemical Formula
C16H16N2O3S
InChI Key
BQSJTQLCZDPROO-UHFFFAOYSA-N
InChI
InChI=1S/C16H16N2O3S/c1-9(2)8-21-13-5-4-11(6-12(13)7-17)15-18-10(3)14(22-15)16(19)20/h4-6,9H,8H2,1-3H3,(H,19,20)
IUPAC Name
2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid
SMILES
CC(C)COC1=C(C=C(C=C1)C1=NC(C)=C(S1)C(O)=O)C#N

Pharmacology

Indication

For the treatment of hyperuricemia in patients with gout.

Associated Conditions
Pharmacodynamics

Febuxostat (ULORIC) is a novel, xanthine oxidase/dehydrogenase (XO/XDH) inhibitor being developed by Teijin, TAP Pharmaceuticals, and Ipsen for the treatment of gout. The currently available XO inhibitor, allopurinol, has been associated with serious instances of severe hypersensitivity, in some cases leading to fatalities. There is some suggestion that febuxostat is less prone to excacerbate systemic inflammatory events in animal studies.

Mechanism of action

Febuxostat, a xanthine oxidase inhibitor, achieves its therapeutic effect by decreasing serum uric acid. Febuxostat is not expected to inhibit other enzymes involved in purine and pyrimidine synthesis and metabolism at therapeutic concentrations.

TargetActionsOrganism
AXanthine dehydrogenase/oxidase
inhibitor
Human
Absorption

>49%

Volume of distribution

The mean apparent steady state volume of distribution (Vss/F) of febuxostat was approximately 50 L (CV ~40%)

Protein binding

99.2%

Metabolism

Febuxostat is extensively metabolized by both conjugation via uridine diphosphate glucuronosyltransferase (UGT) enzymes including UGT1A1, UGT1A3, UGT1A9, and UGT2B7 and oxidation via cytochrome P450 (CYP) enzymes including CYP1A2, 2C8 and 2C9 and non-P450 enzymes. The relative contribution of each enzyme isoform in the metabolism of febuxostat is not clear. The oxidation of the isobutyl side chain leads to the formation of four pharmacologically active hydroxy metabolites, all of which occur in plasma of humans at a much lower extent than febuxostat. In urine and feces, acyl glucuronide metabolites of febuxostat (~35% of the dose), and oxidative metabolites, 67M-1 (~10% of the dose), 67M-2 (~11% of the dose), and 67M-4, a secondary metabolite from 67M-1 (~14% of the dose), appeared to be the major metabolites of febuxostat in vivo.

Route of elimination

Febuxostat is eliminated primarily through both hepatic and renal pathways.

Half life

~5-8 hours.

Clearance
Not Available
Toxicity

The FDA adverse event reporting system database, AERS, indicated potential signals of febuxostat-associated cardiovascular thromboembolic events. AERS is not capable of establishing the causal link and detecting the true frequency of an adverse event associated with a drug. The positive IC value found in this study merits continued surveillance and assessment of cardiovascular thromboembolic events associated with Febuxostat.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
3-isobutyl-1-methyl-7H-xanthineThe serum concentration of the active metabolites of 3-isobutyl-1-methyl-7H-xanthine can be increased when 3-isobutyl-1-methyl-7H-xanthine is used in combination with Febuxostat.
6-O-benzylguanineThe serum concentration of the active metabolites of 6-O-benzylguanine can be increased when 6-O-benzylguanine is used in combination with Febuxostat.
7-DeazaguanineThe serum concentration of the active metabolites of 7-Deazaguanine can be increased when 7-Deazaguanine is used in combination with Febuxostat.
7,9-DimethylguanineThe serum concentration of the active metabolites of 7,9-Dimethylguanine can be increased when 7,9-Dimethylguanine is used in combination with Febuxostat.
8-azaguanineThe serum concentration of the active metabolites of 8-azaguanine can be increased when 8-azaguanine is used in combination with Febuxostat.
8-chlorotheophyllineThe serum concentration of the active metabolites of 8-chlorotheophylline can be increased when 8-chlorotheophylline is used in combination with Febuxostat.
9-DeazaguanineThe serum concentration of the active metabolites of 9-Deazaguanine can be increased when 9-Deazaguanine is used in combination with Febuxostat.
9-MethylguanineThe serum concentration of the active metabolites of 9-Methylguanine can be increased when 9-Methylguanine is used in combination with Febuxostat.
AcefyllineThe serum concentration of the active metabolites of Acefylline can be increased when Acefylline is used in combination with Febuxostat.
AminophyllineThe serum concentration of the active metabolites of Aminophylline can be increased when Aminophylline is used in combination with Febuxostat.
Food Interactions
Not Available

References

Synthesis Reference

EPO Patent Report

General References
  1. Stamp LK, O'Donnell JL, Chapman PT: Emerging therapies in the long-term management of hyperuricaemia and gout. Intern Med J. 2007 Apr;37(4):258-66. [PubMed:17388867]
  2. Pascual E, Sivera F: Therapeutic advances in gout. Curr Opin Rheumatol. 2007 Mar;19(2):122-7. [PubMed:17278926]
  3. Gandhi PK, Gentry WM, Bottorff MB: Cardiovascular thromboembolic events associated with febuxostat: investigation of cases from the FDA adverse event reporting system database. Semin Arthritis Rheum. 2013 Jun;42(6):562-6. doi: 10.1016/j.semarthrit.2012.11.002. Epub 2013 Jan 24. [PubMed:23352248]
  4. Saban-Ruiz J, Alonso-Pacho A, Fabregate-Fuente M, de la Puerta Gonzalez-Quevedo C: Xanthine oxidase inhibitor febuxostat as a novel agent postulated to act against vascular inflammation. Antiinflamm Antiallergy Agents Med Chem. 2013;12(1):94-9. [PubMed:23286293]
  5. Tsuda H, Kawada N, Kaimori JY, Kitamura H, Moriyama T, Rakugi H, Takahara S, Isaka Y: Febuxostat suppressed renal ischemia-reperfusion injury via reduced oxidative stress. Biochem Biophys Res Commun. 2012 Oct 19;427(2):266-72. doi: 10.1016/j.bbrc.2012.09.032. Epub 2012 Sep 17. [PubMed:22995295]
  6. Zhang T, Sun Y, Zhang P, Gao J, Wang S, He Z: Ultra-performance liquid chromatography-tandem mass spectrometry method for the determination of febuxostat in dog plasma and its application to a pharmacokinetic study. Biomed Chromatogr. 2013 Feb;27(2):137-41. doi: 10.1002/bmc.2756. Epub 2012 Jun 27. [PubMed:22736298]
External Links
KEGG Drug
D01206
PubChem Compound
134018
PubChem Substance
310264854
ChemSpider
118173
BindingDB
50320491
ChEBI
31596
ChEMBL
CHEMBL1164729
PharmGKB
PA165958521
HET
TEI
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Febuxostat
ATC Codes
M04AA03 — Febuxostat
AHFS Codes
  • 92:16.00 — Antigout Agents
PDB Entries
1n5x
FDA label
Download (115 KB)
MSDS
Download (568 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceHealthy Volunteers1
1CompletedTreatmentAcute Gouty Arthritis1
1RecruitingTreatmentAcute Gouty Arthritis1
1, 2CompletedBasic ScienceGout and Asymptomatic Hyperuricemia1
1, 2RecruitingPreventionTumour lysis syndrome1
2CompletedDiagnosticAcute Gouty Arthritis1
2CompletedPreventionGout Flares1
2CompletedTreatmentAcute Gouty Arthritis3
2CompletedTreatmentAcute Gouty Arthritis / Hyperuricemia3
2CompletedTreatmentAcute Gouty Arthritis / Moderate Renal Impairment1
2CompletedTreatmentAsymptomatic Hyperuricemia1
2CompletedTreatmentHigh Blood Pressure (Hypertension)1
2CompletedTreatmentHyperuricosuria / Renal Stones1
2CompletedTreatmentImpaired Renal Function1
2CompletedTreatmentJoint Damage1
2Not Yet RecruitingPreventionContrast-Induced Acute Kidney Injury / Prophylaxis of Contrast-induced nephropathy1
2TerminatedTreatmentAnginal Pain1
2, 3CompletedTreatmentEndothelial Dysfunction / Endstage Renal Disease1
3CompletedPreventionTumour lysis syndrome1
3CompletedTreatmentAcute Gouty Arthritis9
3CompletedTreatmentCardiovascular Disease (CVD)1
3CompletedTreatmentHyperuricemia With or Without Gout1
3CompletedTreatmentTophaceous Gout1
4Active Not RecruitingTreatmentAcute Gouty Arthritis1
4Active Not RecruitingTreatmentHyperuricemia / Left Ventricular Diastolic Dysfunction / Metabolic Syndromes1
4CompletedBasic ScienceHigh Blood Pressure (Hypertension)1
4CompletedDiagnosticAcute Gouty Arthritis1
4CompletedTreatment24 Hour Blood Pressure / Acute Gouty Arthritis / High Blood Pressure (Hypertension) / Prehypertension / Pulse Wave Velocity1
4CompletedTreatmentAcute Gouty Arthritis1
4CompletedTreatmentAdenine Phosphoribosyltransferase Deficiency1
4CompletedTreatmentCoronary Artery Disease1
4CompletedTreatmentDiabetes, Diabetes Mellitus Type 11
4CompletedTreatmentHyperuricemia1
4CompletedTreatmentPrimary Gout1
4RecruitingTreatmentAcute Gouty Arthritis / Chronic Kidney Disease (CKD)1
4RecruitingTreatmentChronic Renal Diseases / Hyperuricemia1
4RecruitingTreatmentHyperuricemia1
4TerminatedTreatmentCoronary Artery Disease1
Not AvailableActive Not RecruitingTreatmentHyperuricemia1
Not AvailableCompletedTreatmentChronic Kidney Disease (CKD) / Diabetes Mellitus (DM)1
Not AvailableNot Yet RecruitingTreatmentAbnormal Renal Function / Chronic Kidney Disease (CKD) / Hyperuricemia1
Not AvailableRecruitingBasic ScienceCardiovascular System / Coronary Artery Disease / Endothelial Function / High Blood Pressure (Hypertension) / Metabolic Syndromes / Oxidative Stress1
Not AvailableRecruitingTreatmentAbnormal Renal Function / Chronic Kidney Disease (CKD) / Hyperuricemia1
Not AvailableTerminatedTreatmentAcute Gouty Arthritis / Blood Pressures1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral120 mg
Tablet, film coatedOral80 mg
TabletOral40 mg/1
TabletOral80 mg
TabletOral80 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5614520No1997-03-252019-03-25Us
US8372872No2013-02-122031-09-08Us
US9107912No2015-08-182031-09-08Us
US6225474No2001-05-012019-06-18Us
US7361676No2008-04-222024-03-08Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)238-239°Patent WO2012056442 A1
Predicted Properties
PropertyValueSource
Water Solubility0.0183 mg/mLALOGPS
logP3.8ALOGPS
logP3.52ChemAxon
logS-4.2ALOGPS
pKa (Strongest Acidic)3.08ChemAxon
pKa (Strongest Basic)0.39ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area83.21 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity93.93 m3·mol-1ChemAxon
Polarizability33.88 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9865
Blood Brain Barrier+0.7853
Caco-2 permeable+0.5126
P-glycoprotein substrateNon-substrate0.7834
P-glycoprotein inhibitor INon-inhibitor0.8351
P-glycoprotein inhibitor IINon-inhibitor0.8076
Renal organic cation transporterNon-inhibitor0.8845
CYP450 2C9 substrateNon-substrate0.7229
CYP450 2D6 substrateNon-substrate0.8064
CYP450 3A4 substrateNon-substrate0.5899
CYP450 1A2 substrateInhibitor0.7936
CYP450 2C9 inhibitorInhibitor0.6712
CYP450 2D6 inhibitorNon-inhibitor0.8662
CYP450 2C19 inhibitorInhibitor0.734
CYP450 3A4 inhibitorNon-inhibitor0.7441
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6509
Ames testNon AMES toxic0.7486
CarcinogenicityNon-carcinogens0.8601
BiodegradationNot ready biodegradable0.9401
Rat acute toxicity2.3811 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9964
hERG inhibition (predictor II)Non-inhibitor0.9192
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (42.2 KB)
Spectra
SpectrumSpectrum TypeSplash Key
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/MSsplash10-03xr-0292000000-d8e012f875d1014fe351

Taxonomy

Description
This compound belongs to the class of organic compounds known as thiazolecarboxylic acids and derivatives. These are heterocyclic compounds containing a thiazole ring which bears a carboxylic acid group (or a derivative thereof).
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Azoles
Sub Class
Thiazoles
Direct Parent
Thiazolecarboxylic acids and derivatives
Alternative Parents
Phenoxy compounds / Phenol ethers / Benzonitriles / 2,4,5-trisubstituted thiazoles / Alkyl aryl ethers / Heteroaromatic compounds / Nitriles / Monocarboxylic acids and derivatives / Carboxylic acids / Azacyclic compounds
show 3 more
Substituents
2,4,5-trisubstituted 1,3-thiazole / Phenoxy compound / Benzonitrile / Thiazolecarboxylic acid or derivatives / Phenol ether / Alkyl aryl ether / Monocyclic benzene moiety / Benzenoid / Heteroaromatic compound / Carboxylic acid derivative
show 14 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
nitrile, 1,3-thiazolemonocarboxylic acid (CHEBI:45943)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Xanthine oxidase activity
Specific Function
Key enzyme in purine degradation. Catalyzes the oxidation of hypoxanthine to xanthine. Catalyzes the oxidation of xanthine to uric acid. Contributes to the generation of reactive oxygen species. Ha...
Gene Name
XDH
Uniprot ID
P47989
Uniprot Name
Xanthine dehydrogenase/oxidase
Molecular Weight
146422.99 Da
References
  1. Bruce SP: Febuxostat: a selective xanthine oxidase inhibitor for the treatment of hyperuricemia and gout. Ann Pharmacother. 2006 Dec;40(12):2187-94. Epub 2006 Nov 28. [PubMed:17132810]

Drug created on October 18, 2007 17:30 / Updated on December 14, 2018 17:10