TERIFLUNOMIDE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C12H9F3N2O2
Molecular Weight	270.2073
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 Search

SMILES

C\C(O)=C(/C#N)C(=O)NC1=CC=C(C=C1)C(F)(F)F

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	270.2073
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	1
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 8146		160.0 nM [Ki]
Dihydroorotate dehydrogenase 9 Target ID: CHEMBL1966 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9666414	Inhibitor 8146

Conditions

Condition	Modality	Targets	Highest Phase	Product
Multiple sclerosis 101 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202992s003lbl.pdf	Primary		Approved 8307	AUBAGIO Approved Use Indicated for the treatment of patients with relapsing forms of multiple sclerosis. Launch Date 1.34740797E12
Active rheumatoid arthritis 2 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020905s031lbl.pdf	Palliative		Approved 8307	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 9.0538561E11

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 Page: p.923	unhealthy, 36 n = 250 Health Status: unhealthy Condition: Multiple sclerosis Age Group: 36 Sex: M+F Population Size: 250 Sources: https://pubmed.ncbi.nlm.nih.gov/26865517 Page: p.923	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 Page: p.923
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 Page: p.8,9	unhealthy, 37 Health Status: unhealthy Condition: Multiple sclerosis Age Group: 37 Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf Page: p.8,9	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 Page: p.8,9
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 Page: p.2781	unhealthy, 37.8 ± 9.7 n = 43 Health Status: unhealthy Condition: Multiple sclerosis Age Group: 37.8 ± 9.7 Sex: M+F Population Size: 43 Sources: https://pubmed.ncbi.nlm.nih.gov/30511679 Page: p.2781	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 Page: p.2781
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 Page: p.1	unhealthy Health Status: unhealthy Condition: Multiple sclerosis Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf Page: p.1	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 Page: p.1
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 Page: p.7	unhealthy Health Status: unhealthy Condition: Multiple sclerosis Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf Page: p.7	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 Page: p.7

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 Page: p.923	unhealthy, 36 n = 250 Health Status: unhealthy Condition: Multiple sclerosis Age Group: 36 Sex: M+F Population Size: 250 Sources: https://pubmed.ncbi.nlm.nih.gov/26865517 Page: p.923
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 Page: p.923	unhealthy, 36 n = 250 Health Status: unhealthy Condition: Multiple sclerosis Age Group: 36 Sex: M+F Population Size: 250 Sources: https://pubmed.ncbi.nlm.nih.gov/26865517 Page: p.923
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 Page: p.8,9	unhealthy, 37 Health Status: unhealthy Condition: Multiple sclerosis Age Group: 37 Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf Page: p.8,9
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 Page: p.2781	unhealthy, 37.8 ± 9.7 n = 43 Health Status: unhealthy Condition: Multiple sclerosis Age Group: 37.8 ± 9.7 Sex: M+F Population Size: 43 Sources: https://pubmed.ncbi.nlm.nih.gov/30511679 Page: p.2781
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 Page: p.2781	unhealthy, 37.8 ± 9.7 n = 43 Health Status: unhealthy Condition: Multiple sclerosis Age Group: 37.8 ± 9.7 Sex: M+F Population Size: 43 Sources: https://pubmed.ncbi.nlm.nih.gov/30511679 Page: p.2781
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 Page: p.2781	unhealthy, 37.8 ± 9.7 n = 43 Health Status: unhealthy Condition: Multiple sclerosis Age Group: 37.8 ± 9.7 Sex: M+F Population Size: 43 Sources: https://pubmed.ncbi.nlm.nih.gov/30511679 Page: p.2781
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 Page: p.1	unhealthy Health Status: unhealthy Condition: Multiple sclerosis Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf Page: p.1
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 Page: p.1	unhealthy Health Status: unhealthy Condition: Multiple sclerosis Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf Page: p.1
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 Page: p.1	unhealthy Health Status: unhealthy Condition: Multiple sclerosis Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf Page: p.1
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 Page: p.1	unhealthy Health Status: unhealthy Condition: Multiple sclerosis Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf Page: p.1
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 Page: p.7	unhealthy Health Status: unhealthy Condition: Multiple sclerosis Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202992s006lbl.pdf Page: p.7

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
MolPort	MolPort-005-943-824	https://www.molport.com/shop/molecule-link/MolPort-005-943-824
ZINC	ZINC000013512456	http://zinc15.docking.org/substances/ZINC000013512456
eMolecules	26948188	https://www.emolecules.com/cgi-bin/more?vid=26948188

PubMed

Title	Date	PubMed
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
Slowing of disease progression in rheumatoid arthritis patients during long-term treatment with leflunomide or sulfasalazine.	2001	11469522
Leflunomide and rheumatoid arthritis: new preparation. Neither the safest nor the most effective slow-acting antirheumatic drug.	2001 Apr	11718154
Novel therapies in the treatment of systemic lupus erythematosus.	2001 Aug	11892912
[Leflunomide plus methotrexate. Hope for patients with rheumatoid arthritis].	2001 Aug 23	11561463
Leflunomide-mediated suppression of antiviral antibody and Tcell responses: differential restoration by uridine.	2001 Aug 27	11544436
[New basic therapeutic drugs from the viewpoint of evidence-based therapy].	2001 Dec	11826744
[Evidence-based medicine and applying new therapies in general practice: wish and reality].	2001 Dec	11826740
Progress in the treatment of rheumatoid arthritis.	2001 Dec 12	11735734
Leflunomide Aventis Pharma.	2001 Feb	11816835
Discussion. Treatment algorithm: managing rheumatoid arthritis.	2001 Jul	11729430
Economic and quality-of-life impact of rheumatoid arthritis.	2001 Jul	11729429
Beneficial effects of leflunomide in glucocorticoid- and methotrexate-resistant Takayasu's arteritis.	2001 Jul-Aug	11491512
Hamster cardiac xenografts are protected against antibody mediated damage, early after transplantation to Lewis rats.	2001 Nov	11737849
Rationally designed anti-mitotic agents with pro-apoptotic activity.	2001 Nov	11562303
[Leflunomide--a new disease modifying anti-rheumatic agent].	2001 Nov 10	11876141
Inhibition of angiogenesis-related endothelial activity by the experimental immunosuppressive agent leflunomide.	2001 Nov 15	11707749
Use of leflunomide in human renal transplantation.	2001 Nov 27	11726839
Severe liver damage with leflunomide.	2001 Oct	11824431
[New therapy developments in rheumatoid arthritis].	2001 Oct	11759232
Platelet-derived growth factor receptors: a therapeutic target in solid tumors.	2001 Oct	11740804
Current and emerging lupus treatments.	2001 Oct	11680781
Leflunomide for the treatment of systemic lupus erythematosus: comment on the article by McMurray.	2001 Oct	11642648
Treatment of active rheumatoid arthritis with leflunomide: two year follow up of a double blind, placebo controlled trial versus sulfasalazine.	2001 Oct	11557646
Inhibition of HIV replication by A77 1726, the active metabolite of leflunomide, in combination with pyrimidine nucleoside reverse transcriptase inhibitors.	2001 Oct 1	11588518
Is there a place for leflunomide in the treatment of rheumatoid arthritis?	2001 Oct 13	11675052
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	11596043
Comparison of rheumatoid arthritis care costs in patients starting therapy with leflunomide versus etanercept.	2001 Sep	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 Sep	11592358
Etanercept therapy for immune-mediated cochleovestibular disorders: preliminary results in a pilot study.	2001 Sep	11568668
[Rheumatic pain].	2001 Sep	11554047
Improved functional ability in patients with rheumatoid arthritis--longterm treatment with leflunomide versus sulfasalazine. European Leflunomide Study Group.	2001 Sep	11550964
Suppression of experimental autoimmune neuritis by leflunomide.	2001 Sep	11522581
Modulation of inducible nitric oxide synthase activation by immunosuppressive drugs.	2001 Sep	11513333
[Treatment of rheumatoid arthritis by inhibition of tumor necrosis factor with infliximab or etanercept].	2001 Sep 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 Sep-Oct	11550070
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
Treatment of severe psoriasis and psoriatic arthritis with leflunomide.	2002 Feb	11903256
Comparative assessment of leflunomide and methotrexate for the treatment of rheumatoid arthritis, by dynamic enhanced magnetic resonance imaging.	2002 Feb	11840438
Experiences with leflunomide in solid organ transplantation.	2002 Feb 15	11884931
[Treatment of cutaneous leishmaniasis--an update].	2002 Jan	11851113
Leflunomide induced fevers, thrombocytosis, and leukocytosis in a patient with relapsing polychondritis.	2002 Jan	11824960
Effect of hemodialysis on leflunomide plasma concentrations.	2002 Jan	11816264
Update on the treatment of systemic lupus erythematosus: therapeutic highlights from the Sixth International Lupus Conference.	2002 Jan	11802320
Current treatment of juvenile rheumatoid arthritis.	2002 Jan	11773549

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 `Fri Dec 16 17:58:24 UTC 2022` Edited by `admin` on `Fri Dec 16 17:58:24 UTC 2022`
Record UNII	1C058IKG3B
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

TERIFLUNOMIDE

Official Name

English

TERIFLUNOMIDE [MI]

Common Name

English

teriflunomide [INN]

Common Name

English

AUBAGIO

Brand Name

English

HMR-1726

Code

English

LEFLUNOMIDE RELATED COMPOUND B

Common Name

English

TERIFLUNOMIDE [USAN]

Common Name

English

HMR1726

Code

English

LEFLUNOMIDE RELATED COMPOUND B [USP IMPURITY]

Common Name

English

2-BUTENAMIDE, 2-CYANO-3-HYDROXY-N-(4-(TRIFLUOROMETHYL)PHENYL)-, (2Z)-

Systematic Name

English

LEFLUNOMIDE IMPURITY B [EP IMPURITY]

Common Name

English

TERIFLUNOMIDE [ORANGE BOOK]

Common Name

English

A77 1726

Code

English

TERIFLUNOMIDE [VANDF]

Common Name

English

Teriflunomide [WHO-DD]

Common Name

English

TERIFLUNOMIDE [EP MONOGRAPH]

Common Name

English

LEFLUNOMIDE RELATED COMPOUND B [USP-RS]

Common Name

English

Classification Tree Code System Code

LIVERTOX

NBK548525