Identification

Name
Teriflunomide
Accession Number
DB08880  (EXPT00364, DB03805)
Type
Small Molecule
Groups
Approved
Description

Teriflunomide is the active metabolite of leflunomide, and it acts as an immunomodulatory agent by inhibiting pyrimidine synthesis. It is marketed under the name Aubagio® and is indicated for the treatment of multiple sclerosis, specifically relapsing forms. The FDA label states an important warning about the risk of hepatoxicity and teratogenicity for patients using teriflunomide.

Structure
Thumb
Synonyms
  • (Z)-2-cyano-alpha,alpha,alpha-trifluoro-3-hydroxy-p-crotonotoluidide
  • A 77-1726
  • A 771726
  • A771726
  • HMR 1726
  • Teriflunomida
  • Tériflunomide
  • Teriflunomidum
External IDs
A-771726 / A77 1726 / HMR-1726 / HMR1726
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AubagioTablet, film coated14 mgOralSanofi Aventis Groupe2013-08-26Not applicableEu
AubagioTablet14 mgOralSanofi Genzyme, a Division of Sanofi Aventis Canada Inc2013-11-15Not applicableCanada
AubagioTablet, film coated14 mgOralSanofi Aventis Groupe2013-08-26Not applicableEu
AubagioTablet, film coated14 mgOralSanofi Aventis Groupe2013-08-26Not applicableEu
AubagioTablet, film coated14 mg/1OralGenzyme Corporation2013-05-01Not applicableUs
AubagioTablet, film coated14 mgOralSanofi Aventis Groupe2013-08-26Not applicableEu
AubagioTablet, film coated14 mgOralSanofi Aventis Groupe2013-08-26Not applicableEu
AubagioTablet, film coated7 mg/1OralGenzyme Corporation2013-05-01Not applicableUs
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
TeriflunomideTablet, film coated7 mg/1OralAmneal Pharmaceuticals LLC2018-10-01Not applicableUs
TeriflunomideTablet, film coated14 mg/1OralAmneal Pharmaceuticals LLC2018-10-01Not applicableUs
Categories
UNII
1C058IKG3B
CAS number
163451-81-8
Weight
Average: 270.2073
Monoisotopic: 270.061612157
Chemical Formula
C12H9F3N2O2
InChI Key
UTNUDOFZCWSZMS-YFHOEESVSA-N
InChI
InChI=1S/C12H9F3N2O2/c1-7(18)10(6-16)11(19)17-9-4-2-8(3-5-9)12(13,14)15/h2-5,18H,1H3,(H,17,19)/b10-7-
IUPAC Name
(2Z)-2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]but-2-enamide
SMILES
C\C(O)=C(/C#N)C(=O)NC1=CC=C(C=C1)C(F)(F)F

Pharmacology

Indication

Used in the treatment of relapsing forms of multiple sclerosis (MS).

Associated Conditions
Pharmacodynamics

Teriflunomide is an immunomodulatory agent that decreases the amount of activated CNS lymphocytes, which results in anti-inflammatory and antiproliferative effects.

Mechanism of action

The exact mechanism by which teriflunomide acts in MS is not known. What is known is that teriflunomide prevents pyrimidine synthesis by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase, and this may be involved in its immunomodulatory effect in MS.

TargetActionsOrganism
UDihydroorotate dehydrogenase (quinone), mitochondrial
inhibitor
Human
Absorption

After oral administration of teriflunomide, maximum plasma concentrations are reached, on average, in 1-4 hours.

Volume of distribution

After a single intravenous dose, the volume of distribution is 11 L.

Protein binding

Teriflunomide is extensively plasma protein bound(>99%).

Metabolism

Teriflunomide mainly undergoes hydrolyis to minor metabolites. Other minor metabolic pathways include oxidation, N-acetylation and sulfate conjugation. Teriflunomide is not metabolized by CYP450 or flavin monoamine oxidase.

Route of elimination

Teriflunomide is eliminated unchanged and mainly through bile. Specifically 37.5% is eliminated in the feces and 22.6% in urine.

Half life

The median half-life is 18 to 19 days.

Clearance

After a single IV dose, teriflunomide has a total body clearance of 30.5 mL/h.

Toxicity

Teriflunomide is contraindicated in pregnant women or women of childbearing age due to the risk of teratogenicity. Teriflunomide is also contraindicated in severe hepatic impairment due to reports of hepatotoxicity, hepatic failure, and death.

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

Interactions

Drug Interactions
DrugInteraction
(4R)-limoneneThe risk or severity of adverse effects can be increased when Teriflunomide is combined with (4R)-limonene.
16-BromoepiandrosteroneThe risk or severity of adverse effects can be increased when Teriflunomide is combined with 16-Bromoepiandrosterone.
19-norandrostenedioneThe risk or severity of adverse effects can be increased when Teriflunomide is combined with 19-norandrostenedione.
5-androstenedioneThe risk or severity of adverse effects can be increased when Teriflunomide is combined with 5-androstenedione.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Teriflunomide.
AceclofenacThe risk or severity of adverse effects can be increased when Teriflunomide is combined with Aceclofenac.
AcemetacinThe risk or severity of adverse effects can be increased when Teriflunomide is combined with Acemetacin.
AcenocoumarolThe serum concentration of Acenocoumarol can be decreased when it is combined with Teriflunomide.
AcetaminophenThe serum concentration of Acetaminophen can be decreased when it is combined with Teriflunomide.
Activated charcoalThe serum concentration of Teriflunomide can be decreased when it is combined with Activated charcoal.
Food Interactions
  • Food does not affect teriflunomide pharmacokinetics, so take with or without food.

References

Synthesis Reference

Keshav Deo, Samir Patel, Snehal Dhol, Sunil Sanghani, Vishal Ray, " PROCESS FOR PREPARING TERIFLUNOMIDE." U.S. Patent US20110092727, issued April 21, 2011.

US20110092727
General References
  1. O'Connor PW, Li D, Freedman MS, Bar-Or A, Rice GP, Confavreux C, Paty DW, Stewart JA, Scheyer R: A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology. 2006 Mar 28;66(6):894-900. [PubMed:16567708]
  2. Tallantyre E, Evangelou N, Constantinescu CS: Spotlight on teriflunomide. Int MS J. 2008 Jun;15(2):62-8. [PubMed:18782502]
External Links
KEGG Drug
D10172
PubChem Compound
54684141
PubChem Substance
347827807
ChemSpider
16737143
BindingDB
50018011
ChEBI
68540
ChEMBL
CHEMBL973
HET
A26
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Teriflunomide
ATC Codes
L04AA31 — Teriflunomide
AHFS Codes
  • 92:20.00 — Immunomodulatory Agents
PDB Entries
1d3h / 1tv5
FDA label
Download (527 KB)
MSDS
Download (124 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1TerminatedNot AvailableHealthy Volunteers / Teriflunomide Elimination1
2CompletedNot AvailableDisseminated Sclerosis1
2CompletedTreatmentDisseminated Sclerosis5
3Active Not RecruitingTreatmentDisseminated Sclerosis2
3Active Not RecruitingTreatmentDisseminated Sclerosis / Relapsing Multiple Sclerosis (RMS)1
3Active Not RecruitingTreatmentRelapsing Multiple Sclerosis (RMS)1
3CompletedTreatmentDisseminated Sclerosis5
3RecruitingTreatmentDisseminated Sclerosis1
3RecruitingTreatmentRelapsing Multiple Scelrosis1
3RecruitingTreatmentRelapsing Multiple Sclerosis (RMS)2
3TerminatedTreatmentRelapsing Multiple Sclerosis (RMS)1
4Active Not RecruitingTreatmentDisseminated Sclerosis1
4CompletedTreatmentDisseminated Sclerosis1
4Not Yet RecruitingTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
Not AvailableEnrolling by InvitationNot AvailableRelapsing Remitting Multiple Sclerosis (RRMS)1
Not AvailableNot Yet RecruitingNot AvailableTecfidera / Teriflunomide1
Not AvailableRecruitingNot AvailableRelapsing Remitting Multiple Sclerosis (RRMS)2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral14 mg
Tablet, film coatedOral14 mg/1
Tablet, film coatedOral14 mg
Tablet, film coatedOral7 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6794410No2002-04-152022-04-15Us
US9186346No2014-02-042034-02-04Us
US8802735No2010-09-142030-09-14Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilitySoluble in DMSO (practically insoluble in water).From FDA label.
Predicted Properties
PropertyValueSource
Water Solubility0.0124 mg/mLALOGPS
logP2.3ALOGPS
logP2.14ChemAxon
logS-4.3ALOGPS
pKa (Strongest Acidic)5.48ChemAxon
pKa (Strongest Basic)-3.2ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area73.12 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity64.39 m3·mol-1ChemAxon
Polarizability23.15 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

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 trifluoromethylbenzenes. These are organofluorine compounds that contain a benzene ring substituted with one or more trifluoromethyl groups.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Trifluoromethylbenzenes
Direct Parent
Trifluoromethylbenzenes
Alternative Parents
Anilides / N-arylamides / Vinylogous acids / Secondary carboxylic acid amides / Nitriles / Enols / Organopnictogen compounds / Organofluorides / Organic oxides / Hydrocarbon derivatives
show 2 more
Substituents
Trifluoromethylbenzene / Anilide / N-arylamide / Vinylogous acid / Carboxamide group / Secondary carboxylic acid amide / Carboxylic acid derivative / Enol / Carbonitrile / Nitrile
show 13 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
nitrile, enamide, aromatic amide, enol, (trifluoromethyl)benzenes (CHEBI:68540)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Ubiquinone binding
Specific Function
Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
Gene Name
DHODH
Uniprot ID
Q02127
Uniprot Name
Dihydroorotate dehydrogenase (quinone), mitochondrial
Molecular Weight
42866.93 Da
References
  1. Palmer AM: Teriflunomide, an inhibitor of dihydroorotate dehydrogenase for the potential oral treatment of multiple sclerosis. Curr Opin Investig Drugs. 2010 Nov;11(11):1313-23. [PubMed:21157651]
  2. Davis JP, Cain GA, Pitts WJ, Magolda RL, Copeland RA: The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase. Biochemistry. 1996 Jan 30;35(4):1270-3. [PubMed:8573583]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
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
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
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. Chan A, de Seze J, Comabella M: Teriflunomide in Patients with Relapsing-Remitting Forms of Multiple Sclerosis. CNS Drugs. 2016 Jan;30(1):41-51. doi: 10.1007/s40263-015-0299-y. [PubMed:26758290]
  2. FDA label, Teriflunomide [File]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. Kis E, Nagy T, Jani M, Molnar E, Janossy J, Ujhellyi O, Nemet K, Heredi-Szabo K, Krajcsi P: Leflunomide and its metabolite A771726 are high affinity substrates of BCRP: implications for drug resistance. Ann Rheum Dis. 2009 Jul;68(7):1201-7. doi: 10.1136/ard.2007.086264. Epub 2008 Apr 8. [PubMed:18397960]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da

Drug created on May 19, 2013 20:55 / Updated on October 16, 2018 08:40