U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ACHIRAL
Molecular Formula C12H9F3N2O2
Molecular Weight 270.2077
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 1
Charge 0
Stereo Comments Teriflunomide then can interconvert between the E and Z enolic forms (and the corresponding keto-amide), with the Z-enol being the most stable and therefore most predominant form (https://en.wikipedia.org/wiki/Leflunomide)

SHOW SMILES / InChI
Structure of TERIFLUNOMIDE

SMILES

C/C(=C(\C#N)/C(=O)Nc1ccc(cc1)C(F)(F)F)/O

InChI

InChIKey=UTNUDOFZCWSZMS-YFHOEESVSA-N
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-

HIDE SMILES / InChI

Molecular Formula C12H9F3N2O2
Molecular Weight 270.2077
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 1
Optical Activity NONE

Description
Curator's Comment:: https://clinicaltrials.gov/ct2/show/NCT00622700?term=teriflunomide&rank=8

Teriflunomide (trade name Aubagio, marketed by Sanofi) is the active metabolite of leflunomide and it acts as an immunomodulatory agent by inhibiting pyrimidine synthesis by blocking the enzyme dihydroorotate dehydrogenase. Teriflunomide was investigated in the Phase III clinical trial TEMSO as a medication for multiple sclerosis (MS). The drug was approved by the FDA on September 13, 2012 and in the European Union on August 26, 2013. It is uncertain whether this explains its effect on MS lesions. Teriflunomide inhibits rapidly dividing cells, including activated T cells, which are thought to drive the disease process in MS. Teriflunomide may decrease the risk of infections compared to chemotherapy-like drugs because of its more-limited effects on the immune system. It has been found that teriflunomide blocks the transcription factor NF-κB. It also inhibits tyrosine kinase enzymes, but only in high doses not clinically used.

CNS Activity

Curator's Comment:: Has only limited penetration across the blood–brain barrier

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
Target ID: Q02127
Gene ID: 1723
Gene Symbol: DHODH
Target Organism: Homo sapiens (Human)
160 nM [Ki]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
AUBAGIO

Approved Use

Indicated for the treatment of patients with relapsing forms of multiple sclerosis.

Launch Date

1347408000000
Palliative
ARAVA

Approved Use

Leflunomide is indicated in adults for the treatment of active rheumatoid arthritis (RA): to reduce signs and symptoms to inhibit structural damage as evidenced by X-ray erosions and joint space narrowing to improve physical function (see CLINICAL STUDIES ). Aspirin, nonsteroidal anti-inflammatory agents and/or low dose corticosteroids may be continued during treatment with leflunomide (see PRECAUTIONS: Drug Interactions: NSAIDs ). The combined use of leflunomide with antimalarials, intramuscular or oral gold, D penicillamine, azathioprine, or methotrexate has not been adequately studied (see WARNINGS: Immunosuppression Potential/Bone Marrow Suppression ).

Launch Date

905385600000
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
1.06 μg/mL
7 mg single, oral
dose: 7 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TERIFLUNOMIDE plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
100 μg × h/mL
7 mg single, oral
dose: 7 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TERIFLUNOMIDE plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
243 h
7 mg single, oral
dose: 7 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TERIFLUNOMIDE plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
1%
TERIFLUNOMIDE plasma
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
14 mg 1 times / day multiple, oral
Recommended
Dose: 14 mg, 1 times / day
Route: oral
Route: multiple
Dose: 14 mg, 1 times / day
Sources:
unhealthy, 36
Health Status: unhealthy
Age Group: 36
Sex: M+F
Sources:
Disc. AE: ALT increased, Hepatic enzyme increased...
AEs leading to
discontinuation/dose reduction:
ALT increased (3.6%)
Hepatic enzyme increased (0.4%)
Sources:
14 mg 1 times / day multiple, oral
Recommended
Dose: 14 mg, 1 times / day
Route: oral
Route: multiple
Dose: 14 mg, 1 times / day
Sources:
unhealthy, 37
Health Status: unhealthy
Age Group: 37
Sex: M+F
Sources:
Disc. AE: ALT increased...
AEs leading to
discontinuation/dose reduction:
ALT increased (2.6%)
Sources:
14 mg 1 times / day multiple, oral
Recommended
Dose: 14 mg, 1 times / day
Route: oral
Route: multiple
Dose: 14 mg, 1 times / day
Sources:
unhealthy, 37.8 ± 9.7
Health Status: unhealthy
Age Group: 37.8 ± 9.7
Sex: M+F
Sources:
Disc. AE: ALT increased, AST increased...
AEs leading to
discontinuation/dose reduction:
ALT increased (4.7%)
AST increased (4.7%)
Neutropenia (4.7%)
Sources:
672 mg single, oral
Overdose
Dose: 672 mg
Route: oral
Route: single
Dose: 672 mg
Sources:
unknown
Health Status: unknown
Sources:
14 mg 1 times / day multiple, oral
Recommended
Dose: 14 mg, 1 times / day
Route: oral
Route: multiple
Dose: 14 mg, 1 times / day
Sources:
unhealthy
Disc. AE: Peripheral neuropathy...
AEs leading to
discontinuation/dose reduction:
Peripheral neuropathy (1.9%)
Sources:
14 mg 1 times / day multiple, oral
Recommended
Dose: 14 mg, 1 times / day
Route: oral
Route: multiple
Dose: 14 mg, 1 times / day
Sources:
unhealthy
Disc. AE: Hepatotoxicity, Liver injury...
AEs leading to
discontinuation/dose reduction:
Hepatotoxicity
Liver injury (severe)
Liver failure (grade 5)
Disorder fetal
Sources:
AEs

AEs

AESignificanceDosePopulation
Hepatic enzyme increased 0.4%
Disc. AE
14 mg 1 times / day multiple, oral
Recommended
Dose: 14 mg, 1 times / day
Route: oral
Route: multiple
Dose: 14 mg, 1 times / day
Sources:
unhealthy, 36
Health Status: unhealthy
Age Group: 36
Sex: M+F
Sources:
ALT increased 3.6%
Disc. AE
14 mg 1 times / day multiple, oral
Recommended
Dose: 14 mg, 1 times / day
Route: oral
Route: multiple
Dose: 14 mg, 1 times / day
Sources:
unhealthy, 36
Health Status: unhealthy
Age Group: 36
Sex: M+F
Sources:
ALT increased 2.6%
Disc. AE
14 mg 1 times / day multiple, oral
Recommended
Dose: 14 mg, 1 times / day
Route: oral
Route: multiple
Dose: 14 mg, 1 times / day
Sources:
unhealthy, 37
Health Status: unhealthy
Age Group: 37
Sex: M+F
Sources:
ALT increased 4.7%
Disc. AE
14 mg 1 times / day multiple, oral
Recommended
Dose: 14 mg, 1 times / day
Route: oral
Route: multiple
Dose: 14 mg, 1 times / day
Sources:
unhealthy, 37.8 ± 9.7
Health Status: unhealthy
Age Group: 37.8 ± 9.7
Sex: M+F
Sources:
AST increased 4.7%
Disc. AE
14 mg 1 times / day multiple, oral
Recommended
Dose: 14 mg, 1 times / day
Route: oral
Route: multiple
Dose: 14 mg, 1 times / day
Sources:
unhealthy, 37.8 ± 9.7
Health Status: unhealthy
Age Group: 37.8 ± 9.7
Sex: M+F
Sources:
Neutropenia 4.7%
Disc. AE
14 mg 1 times / day multiple, oral
Recommended
Dose: 14 mg, 1 times / day
Route: oral
Route: multiple
Dose: 14 mg, 1 times / day
Sources:
unhealthy, 37.8 ± 9.7
Health Status: unhealthy
Age Group: 37.8 ± 9.7
Sex: M+F
Sources:
Peripheral neuropathy 1.9%
Disc. AE
14 mg 1 times / day multiple, oral
Recommended
Dose: 14 mg, 1 times / day
Route: oral
Route: multiple
Dose: 14 mg, 1 times / day
Sources:
unhealthy
Disorder fetal Disc. AE
14 mg 1 times / day multiple, oral
Recommended
Dose: 14 mg, 1 times / day
Route: oral
Route: multiple
Dose: 14 mg, 1 times / day
Sources:
unhealthy
Hepatotoxicity Disc. AE
14 mg 1 times / day multiple, oral
Recommended
Dose: 14 mg, 1 times / day
Route: oral
Route: multiple
Dose: 14 mg, 1 times / day
Sources:
unhealthy
Liver failure grade 5
Disc. AE
14 mg 1 times / day multiple, oral
Recommended
Dose: 14 mg, 1 times / day
Route: oral
Route: multiple
Dose: 14 mg, 1 times / day
Sources:
unhealthy
Liver injury severe
Disc. AE
14 mg 1 times / day multiple, oral
Recommended
Dose: 14 mg, 1 times / day
Route: oral
Route: multiple
Dose: 14 mg, 1 times / day
Sources:
unhealthy
PubMed

PubMed

TitleDatePubMed
Vasculitis occurring during leflunomide therapy.
2001
The heterotopic tracheal allograft as an animal model of obliterative bronchiolitis.
2001
A randomized, controlled, single-blind trial of leflunomide in the treatment of rheumatoid arthritis.
2001
New therapeutic approaches to the management of rheumatoid arthritis.
2001
Benefits of leflunomide in systemic lupus erythematosus: a pilot observational study.
2001
Slowing of disease progression in rheumatoid arthritis patients during long-term treatment with leflunomide or sulfasalazine.
2001
Bone loss. Therapeutic approaches for preventing bone loss in inflammatory arthritis.
2001
Leflunomide and rheumatoid arthritis: new preparation. Neither the safest nor the most effective slow-acting antirheumatic drug.
2001 Apr
Novel therapies in the treatment of systemic lupus erythematosus.
2001 Aug
[Leflunomide plus methotrexate. Hope for patients with rheumatoid arthritis].
2001 Aug 23
[New basic therapeutic drugs from the viewpoint of evidence-based therapy].
2001 Dec
[Evidence-based medicine and applying new therapies in general practice: wish and reality].
2001 Dec
Progress in the treatment of rheumatoid arthritis.
2001 Dec 12
Leflunomide Aventis Pharma.
2001 Feb
[Application of leflunomide in the treatment of patients with rheumatoid arthritis].
2001 Feb
[Leflunomide--the first specific disease-modifying drug against rheumatoid arthritis].
2001 Feb 7
Discussion. Treatment algorithm: managing rheumatoid arthritis.
2001 Jul
Economic and quality-of-life impact of rheumatoid arthritis.
2001 Jul
Beneficial effects of leflunomide in glucocorticoid- and methotrexate-resistant Takayasu's arteritis.
2001 Jul-Aug
Treating early rheumatoid arthritis in the younger patient.
2001 Jun
[Chronic polyarthritis].
2001 May 24
Hamster cardiac xenografts are protected against antibody mediated damage, early after transplantation to Lewis rats.
2001 Nov
Rationally designed anti-mitotic agents with pro-apoptotic activity.
2001 Nov
[Leflunomide--a new disease modifying anti-rheumatic agent].
2001 Nov 10
Inhibition of angiogenesis-related endothelial activity by the experimental immunosuppressive agent leflunomide.
2001 Nov 15
Use of leflunomide in human renal transplantation.
2001 Nov 27
Augmentation of apoptosis responses in p53-deficient L1210 cells by compounds directed at blocking NFkappaB activation.
2001 Nov-Dec
[New therapy developments in rheumatoid arthritis].
2001 Oct
Platelet-derived growth factor receptors: a therapeutic target in solid tumors.
2001 Oct
Treatment of active rheumatoid arthritis with leflunomide: two year follow up of a double blind, placebo controlled trial versus sulfasalazine.
2001 Oct
Inhibition of HIV replication by A77 1726, the active metabolite of leflunomide, in combination with pyrimidine nucleoside reverse transcriptase inhibitors.
2001 Oct 1
Is there a place for leflunomide in the treatment of rheumatoid arthritis?
2001 Oct 13
Nerve injury proximal or distal to the DRG induces similar spinal glial activation and selective cytokine expression but differential behavioral responses to pharmacologic treatment.
2001 Oct 15
Comparison of rheumatoid arthritis care costs in patients starting therapy with leflunomide versus etanercept.
2001 Sep
Etanercept therapy for immune-mediated cochleovestibular disorders: preliminary results in a pilot study.
2001 Sep
[Rheumatic pain].
2001 Sep
Improved functional ability in patients with rheumatoid arthritis--longterm treatment with leflunomide versus sulfasalazine. European Leflunomide Study Group.
2001 Sep
Suppression of experimental autoimmune neuritis by leflunomide.
2001 Sep
Modulation of inducible nitric oxide synthase activation by immunosuppressive drugs.
2001 Sep
[Treatment of rheumatoid arthritis by inhibition of tumor necrosis factor with infliximab or etanercept].
2001 Sep 29
Leflunomide metabolite analogue alpha-cyano-beta-hydroxy-beta-methyl-N-[3-(trifluoromethyl)phenyl]propenamide inhibits IgE/FcepsilonRI receptor-mediated mast cell leukotriene release and allergic asthma in mice.
2001 Sep-Oct
Treating rheumatoid arthritis with new disease modifying drugs.
2002
Treatment of severe psoriasis and psoriatic arthritis with leflunomide.
2002 Feb
Comparative assessment of leflunomide and methotrexate for the treatment of rheumatoid arthritis, by dynamic enhanced magnetic resonance imaging.
2002 Feb
Experiences with leflunomide in solid organ transplantation.
2002 Feb 15
[Treatment of cutaneous leishmaniasis--an update].
2002 Jan
Leflunomide induced fevers, thrombocytosis, and leukocytosis in a patient with relapsing polychondritis.
2002 Jan
Effect of hemodialysis on leflunomide plasma concentrations.
2002 Jan
Current treatment of juvenile rheumatoid arthritis.
2002 Jan
Patents

Sample Use Guides

20 mg once daily
Route of Administration: Oral
Cell cultures were inoculated with feline herpesvirus-1 (FHV-1) and treated simultaneously with concentrations of A77 (active metabolite of leflunomide, A77 1726) ranging from 0 to 200 uM. Concentrations of A77 > or = 20 uM were associated with substantial reduction in plaque number and viral load. Concentrations > or = 100 uM were associated with complete suppression of plaque formation. At low concentrations of A77, clusters of intracytoplasmic virus particles that appeared to lack tegument and an external membrane were detected.
Substance Class Chemical
Created
by admin
on Fri Jun 25 21:06:28 UTC 2021
Edited
by admin
on Fri Jun 25 21:06:28 UTC 2021
Record UNII
1C058IKG3B
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
TERIFLUNOMIDE
DASH   INN   MI   ORANGE BOOK   USAN   VANDF   WHO-DD  
INN   USAN  
Official Name English
LEFLUNOMIDE SPECIFIED IMPURITY B [EP]
Common Name English
LEFLUNOMIDE RELATED COMPOUND B [USP]
Common Name English
TERIFLUNOMIDE [MI]
Common Name English
TERIFLUNOMIDE [INN]
Common Name English
AUBAGIO
Brand Name English
HMR-1726
Code English
LEFLUNOMIDE RELATED COMPOUND B
USP  
Common Name English
TERIFLUNOMIDE [USAN]
Common Name English
HMR1726
Code English
TERIFLUNOMIDE [WHO-DD]
Common Name English
LEFLUNOMIDE RELATED COMPOUND B RS [USP]
Common Name English
2-BUTENAMIDE, 2-CYANO-3-HYDROXY-N-(4-(TRIFLUOROMETHYL)PHENYL)-, (2Z)-
Systematic Name English
TERIFLUNOMIDE [ORANGE BOOK]
Common Name English
A77 1726
Code English
TERIFLUNOMIDE [VANDF]
Common Name English
TERIFLUNOMIDE [EP MONOGRAPH]
Common Name English
LEFLUNOMIDE RELATED COMPOUND B [USP-RS]
Common Name English
Classification Tree Code System Code
LIVERTOX 940
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
WHO-VATC QL04AA31
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
NCI_THESAURUS C471
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
EMA ASSESSMENT REPORTS AUBAGIO (AUTHORIZED: MULTIPLE SCLEROSIS)
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
NDF-RT N0000185502
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
WHO-ATC L04AA31
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
Code System Code Type Description
DRUG BANK
DB08880
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
PRIMARY
PUBCHEM
54684141
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
PRIMARY
EVMPD
SUB25218
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
PRIMARY
MESH
C527525
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
PRIMARY
WIKIPEDIA
TERIFLUNOMIDE
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
PRIMARY
FDA UNII
1C058IKG3B
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
PRIMARY
LACTMED
Teriflunomide
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
PRIMARY
INN
7761
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
PRIMARY
NDF-RT
N0000185501
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
PRIMARY Dihydroorotate Dehydrogenase Inhibitors [MoA]
MERCK INDEX
M10578
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
PRIMARY Merck Index
ChEMBL
CHEMBL973
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
PRIMARY
CAS
108605-62-5
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
NON-SPECIFIC STEREOCHEMISTRY
NCI_THESAURUS
C76662
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
PRIMARY
USP_CATALOG
1357056
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
PRIMARY USP-RS
DRUG CENTRAL
4634
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
PRIMARY
IUPHAR
6844
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
PRIMARY
RXCUI
1310520
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
PRIMARY RxNorm
CAS
163451-81-8
Created by admin on Fri Jun 25 21:06:28 UTC 2021 , Edited by admin on Fri Jun 25 21:06:28 UTC 2021
PRIMARY
Related Record Type Details
METABOLIC ENZYME -> NON-SUBSTRATE
METABOLIC ENZYME -> NON-SUBSTRATE
EXCRETED UNCHANGED
FECAL
TRANSPORTER -> INHIBITOR
Terifluniomide is an inhibitor of BCRP, OAT3, OATP1B1, OCT2 in vitro
TRANSPORTER -> INHIBITOR
Terifluniomide is an inhibitor of BCRP, OAT3, OATP1B1, OCT2 in vitro
EXCRETED UNCHANGED
URINE
TRANSPORTER -> INHIBITOR
Terifluniomide is an inhibitor of BCRP, OAT3, OATP1B1, OCT2 in vitro
TARGET -> INHIBITOR
INHIBITOR
IC50
METABOLIC ENZYME -> NON-SUBSTRATE
METABOLIC ENZYME -> NON-SUBSTRATE
METABOLIC ENZYME -> NON-SUBSTRATE
METABOLIC ENZYME -> NON-SUBSTRATE
TRANSPORTER -> INHIBITOR
Terifluniomide is an inhibitor of BCRP, OAT3, OATP1B1, OCT2 in vitro
TRANSPORTER -> SUBSTRATE
Teriflunomide is a substrate of BCRP in vitro
METABOLIC ENZYME -> NON-SUBSTRATE
METABOLIC ENZYME -> NON-SUBSTRATE
BINDER->LIGAND
BINDING
METABOLIC ENZYME -> NON-SUBSTRATE
METABOLIC ENZYME -> NON-SUBSTRATE
Related Record Type Details
METABOLITE -> PARENT
METABOLITE -> PARENT
4-TFMA was not detected in the single dose metabolism study, but was detected in very small amount after repeated dosing in clinical trials 4-TFMA plasma concentrations were measurable at relatively low concentrations after repeated teriflunomide doses of 7 mg (?1.7 ng/mL) and 14 mg (?5.31 ng/mL) for 468 weeks.
MINOR
PRODRUG -> METABOLITE ACTIVE
Related Record Type Details
PARENT -> IMPURITY
CHROMATOGRAPHIC PURITY (HPLC/UV)
USP
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Biological Half-life PHARMACOKINETIC DOSE

Tmax PHARMACOKINETIC ORAL ADMINISTRATION