Leflunomide

Details

Stereochemistry	ACHIRAL
Molecular Formula	C12H9F3N2O2
Molecular Weight	270.2073
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC1=C(C=NO1)C(=O)NC2=CC=C(C=C2)C(F)(F)F

InChI

InChIKey=VHOGYURTWQBHIL-UHFFFAOYSA-N

InChI=1S/C12H9F3N2O2/c1-7-10(6-16-19-7)11(18)17-9-4-2-8(3-5-9)12(13,14)15/h2-6H,1H3,(H,17,18)

HIDE SMILES / InChI

Molecular Formula	C12H9F3N2O2
Molecular Weight	270.2073
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020905s031lbl.pdfhttp://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202992s003lbl.pdf
Curator's Comment: description was created based on several sources, including 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

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Dihydroorotate dehydrogenase (quinone), mitochondrial 3 Target ID: Q02127 Gene ID: 1723.0 Gene Symbol: DHODH Target Organism: Homo sapiens (Human) Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202992s003lbl.pdf	Inhibitor 8504		160.0 nM [Ki]
Dihydroorotate dehydrogenase 10 Target ID: CHEMBL1966 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9666414	Inhibitor 8504

Conditions

Condition	Modality	Targets	Highest Phase	Product
Multiple sclerosis 107 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202992s003lbl.pdf	Primary		Approved 8583	AUBAGIO Approved Use Indicated for the treatment of patients with relapsing forms of multiple sclerosis. Launch Date 2012
Active rheumatoid arthritis 2 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020905s031lbl.pdf	Palliative		Approved 8583	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 1998

C_max

Value	Dose	Co-administered	Analyte	Population
1.06 μg/mL EXPERIMENT https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202992Orig1s000ClinpharmR.pdf	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

Value	Dose	Co-administered	Analyte	Population
100 μg × h/mL EXPERIMENT https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202992Orig1s000ClinpharmR.pdf	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

T_1/2

Value	Dose	Co-administered	Analyte	Population
243 h EXPERIMENT https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202992Orig1s000ClinpharmR.pdf	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

F_unbound

Value	Dose	Co-administered	Analyte	Population
1% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202992s000lbl.pdf			TERIFLUNOMIDE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse 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: https://pubmed.ncbi.nlm.nih.gov/26865517	unhealthy, 36 Health Status: unhealthy Age Group: 36 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/26865517	Disc. AE: ALT increased, Hepatic enzyme increased... AEs leading to discontinuation/dose reduction: ALT increased (3.6%) Hepatic enzyme increased (0.4%) Sources: https://pubmed.ncbi.nlm.nih.gov/26865517
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf	unhealthy, 37 Health Status: unhealthy Age Group: 37 Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf	Disc. AE: ALT increased... AEs leading to discontinuation/dose reduction: ALT increased (2.6%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf
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: https://pubmed.ncbi.nlm.nih.gov/30511679	unhealthy, 37.8 ± 9.7 Health Status: unhealthy Age Group: 37.8 ± 9.7 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/30511679	Disc. AE: ALT increased, AST increased... AEs leading to discontinuation/dose reduction: ALT increased (4.7%) AST increased (4.7%) Neutropenia (4.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/30511679
672 mg single, oral Overdose Dose: 672 mg Route: oral Route: single Dose: 672 mg Sources: https://pubmed.ncbi.nlm.nih.gov/33421160	unknown Health Status: unknown Sources: https://pubmed.ncbi.nlm.nih.gov/33421160	Sources: https://pubmed.ncbi.nlm.nih.gov/33421160
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf	Disc. AE: Hepatotoxicity, Liver injury... AEs leading to discontinuation/dose reduction: Hepatotoxicity Liver injury (severe) Liver failure (grade 5) Disorder fetal Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf	Disc. AE: Peripheral neuropathy... AEs leading to discontinuation/dose reduction: Peripheral neuropathy (1.9%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf

AEs

AE	Significance	Dose	Population
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: https://pubmed.ncbi.nlm.nih.gov/26865517	unhealthy, 36 Health Status: unhealthy Age Group: 36 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/26865517
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: https://pubmed.ncbi.nlm.nih.gov/26865517	unhealthy, 36 Health Status: unhealthy Age Group: 36 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/26865517
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf	unhealthy, 37 Health Status: unhealthy Age Group: 37 Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf
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: https://pubmed.ncbi.nlm.nih.gov/30511679	unhealthy, 37.8 ± 9.7 Health Status: unhealthy Age Group: 37.8 ± 9.7 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/30511679
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: https://pubmed.ncbi.nlm.nih.gov/30511679	unhealthy, 37.8 ± 9.7 Health Status: unhealthy Age Group: 37.8 ± 9.7 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/30511679
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: https://pubmed.ncbi.nlm.nih.gov/30511679	unhealthy, 37.8 ± 9.7 Health Status: unhealthy Age Group: 37.8 ± 9.7 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/30511679
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:68540	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:68540
ChemicalBook	CB02486749	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB02486749
ChemicalBook	CB5648113	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB5648113
ChemicalBook	CB6464433	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB6464433
eMolecules	26948188	https://www.emolecules.com/cgi-bin/more?vid=26948188
MolPort	MolPort-005-943-824	https://www.molport.com/shop/molecule-link/MolPort-005-943-824
ZINC	ZINC000013512456	http://zinc15.docking.org/substances/ZINC000013512456

PubMed

Title	Date	PubMed
Augmentation of apoptosis responses in p53-deficient L1210 cells by compounds directed at blocking NFkappaB activation.	2002-03-26	11911251
Experiences with leflunomide in solid organ transplantation.	2002-02-15	11884931
Treatment of severe psoriasis and psoriatic arthritis with leflunomide.	2002-02	11903256
Comparative assessment of leflunomide and methotrexate for the treatment of rheumatoid arthritis, by dynamic enhanced magnetic resonance imaging.	2002-02	11840438
[Treatment of cutaneous leishmaniasis--an update].	2002-01	11851113
Leflunomide induced fevers, thrombocytosis, and leukocytosis in a patient with relapsing polychondritis.	2002-01	11824960
Effect of hemodialysis on leflunomide plasma concentrations.	2002-01	11816264
Update on the treatment of systemic lupus erythematosus: therapeutic highlights from the Sixth International Lupus Conference.	2002-01	11802320
Current treatment of juvenile rheumatoid arthritis.	2002-01	11773549
Treating rheumatoid arthritis with new disease modifying drugs.	2002	11899752
Economic comparison of leflunomide and methotrexate in patients with rheumatoid arthritis: an evaluation based on a 1-year randomised controlled trial.	2002	11817993
Progress in the treatment of rheumatoid arthritis.	2001-12-12	11735734
[New basic therapeutic drugs from the viewpoint of evidence-based therapy].	2001-12	11826744
[Evidence-based medicine and applying new therapies in general practice: wish and reality].	2001-12	11826740
Use of leflunomide in human renal transplantation.	2001-11-27	11726839
Inhibition of angiogenesis-related endothelial activity by the experimental immunosuppressive agent leflunomide.	2001-11-15	11707749
[Leflunomide--a new disease modifying anti-rheumatic agent].	2001-11-10	11876141
Hamster cardiac xenografts are protected against antibody mediated damage, early after transplantation to Lewis rats.	2001-11	11737849
Rationally designed anti-mitotic agents with pro-apoptotic activity.	2001-11	11562303
Nerve injury proximal or distal to the DRG induces similar spinal glial activation and selective cytokine expression but differential behavioral responses to pharmacologic treatment.	2001-10-15	11596043
Is there a place for leflunomide in the treatment of rheumatoid arthritis?	2001-10-13	11675052
Inhibition of HIV replication by A77 1726, the active metabolite of leflunomide, in combination with pyrimidine nucleoside reverse transcriptase inhibitors.	2001-10-01	11588518
Severe liver damage with leflunomide.	2001-10	11824431
[New therapy developments in rheumatoid arthritis].	2001-10	11759232
Platelet-derived growth factor receptors: a therapeutic target in solid tumors.	2001-10	11740804
Current and emerging lupus treatments.	2001-10	11680781
Leflunomide for the treatment of systemic lupus erythematosus: comment on the article by McMurray.	2001-10	11642648
Treatment of active rheumatoid arthritis with leflunomide: two year follow up of a double blind, placebo controlled trial versus sulfasalazine.	2001-10	11557646
[Treatment of rheumatoid arthritis by inhibition of tumor necrosis factor with infliximab or etanercept].	2001-09-29	11605312
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.	2001-09-11	11550070
Comparison of rheumatoid arthritis care costs in patients starting therapy with leflunomide versus etanercept.	2001-09	11594238
Two-year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate. Utilization of Leflunomide in the Treatment of Rheumatoid Arthritis Trial Investigator Group.	2001-09	11592358
Etanercept therapy for immune-mediated cochleovestibular disorders: preliminary results in a pilot study.	2001-09	11568668
[Rheumatic pain].	2001-09	11554047
Improved functional ability in patients with rheumatoid arthritis--longterm treatment with leflunomide versus sulfasalazine. European Leflunomide Study Group.	2001-09	11550964
Suppression of experimental autoimmune neuritis by leflunomide.	2001-09	11522581
Modulation of inducible nitric oxide synthase activation by immunosuppressive drugs.	2001-09	11513333
Leflunomide-mediated suppression of antiviral antibody and Tcell responses: differential restoration by uridine.	2001-08-27	11544436
[Leflunomide plus methotrexate. Hope for patients with rheumatoid arthritis].	2001-08-23	11561463
Novel therapies in the treatment of systemic lupus erythematosus.	2001-08	11892912
Discussion. Treatment algorithm: managing rheumatoid arthritis.	2001-07	11729430
Economic and quality-of-life impact of rheumatoid arthritis.	2001-07	11729429
Leflunomide and rheumatoid arthritis: new preparation. Neither the safest nor the most effective slow-acting antirheumatic drug.	2001-04	11718154
Leflunomide Aventis Pharma.	2001-02	11816835
[Application of leflunomide in the treatment of patients with rheumatoid arthritis].	2001-02	11505754
Vasculitis occurring during leflunomide therapy.	2001	11701983
The heterotopic tracheal allograft as an animal model of obliterative bronchiolitis.	2001	11686882
A clinical and economic review of disease-modifying antirheumatic drugs.	2001	11548909
A randomized, controlled, single-blind trial of leflunomide in the treatment of rheumatoid arthritis.	2001	11523255
New therapeutic approaches to the management of rheumatoid arthritis.	2001	11520249

Patents

Sample Use Guides

In Vivo Use Guide

20 mg once daily

Route of Administration: Oral

In Vitro Use Guide

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 `Mon Mar 31 18:00:41 GMT 2025` Edited by `admin` on `Mon Mar 31 18:00:41 GMT 2025`
Record UNII	G162GK9U4W
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

Leflunomide

Official Name

English

L04AA13

Preferred Name

English

leflunomide [INN]

Common Name

English

LEFLUNOMIDE [USP-RS]

Common Name

English

LEFLUNOMIDE WINTHROP

Brand Name

English

LEFLUNOMIDE RATIOPHARM

Brand Name

English

LEFLUNOMIDE [USAN]

Common Name

English

LEFLUNOMIDE [USP MONOGRAPH]

Common Name

English

ARAVA

Brand Name

English

HWA-486

Code

English

SULOL

Code

English

Leflunomide [WHO-DD]

Common Name

English

LEFLUNOMIDE [JAN]

Common Name

English

LEFLUNOMIDE TEVA

Brand Name

English

NSC-759864

Code

English

LEFLUNOMIDE [EP IMPURITY]

Common Name

English

SU101

Code

English

LEFLUNOMIDE [MART.]

Common Name

English

NSC-677411

Code

English

LEFLUNOMIDE [EMA EPAR]

Common Name

English

LEFLUNOMIDE [HSDB]

Common Name

English

REPSO

Brand Name

English

LEFLUNOMIDE MEDAC

Brand Name

English

LEFLUNOMIDE [ORANGE BOOK]

Common Name

English

N-(4-(TRIFLUOROMETHYL)PHENYL) 5 METHYLISOXAZOLE-4-CARBOXAMIDE

Systematic Name

English

LEFLUNOMIDE [MI]

Common Name

English

LEFLUNOMIDE [EP MONOGRAPH]

Common Name

English

SU-101

Code

English

4-ISOXAZOLECARBOXAMIDE, 5-METHYL-N-(4-(TRIFLUOROMETHYL)PHENYL)-

Systematic Name

English

LEFLUNOMIDE [VANDF]

Common Name

English

Classification Tree Code System Code

EMA ASSESSMENT REPORTS

LEFLUNOMIDE RATIOPHARM (AUTHORIZED: ARTHITIS, RHEUMATOID)