TERIFLUNOMIDE

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 Search

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

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 7728		160.0 nM [Ki]
Dihydroorotate dehydrogenase 8 Target ID: CHEMBL1966 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9666414	Inhibitor 7728

Conditions

Condition	Modality	Targets	Highest Phase	Product
Multiple sclerosis 95 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202992s003lbl.pdf	Primary		Approved 8043	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 8043	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
Structural and functional comparison of agents interfering with dihydroorotate, succinate and NADH oxidation of rat liver mitochondria.	1998 Oct 15	9776318
Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-kappa B activation and gene expression.	1999 Feb 15	9973483
Leflunomide, a novel immunomodulator for the treatment of active rheumatoid arthritis.	1999 Nov	10890256
The use of leflunomide in the treatment of rheumatoid arthritis: an experimental and clinical review.	2000 May	10878295
Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases.	2000 May	10878294
Immunosuppressive drugs: the first 50 years and a glance forward.	2000 May	10878284
Serious liver disease in a patient receiving methotrexate and leflunomide.	2000 Nov	11083289
Leflunomide: mode of action in the treatment of rheumatoid arthritis.	2000 Nov	11053058
Vasculitis occurring during leflunomide therapy.	2001	11701983
The heterotopic tracheal allograft as an animal model of obliterative bronchiolitis.	2001	11686882
Bone loss. Therapeutic approaches for preventing bone loss in inflammatory arthritis.	2001	11438040
Diabetic rats transplanted with adult porcine islets and immunosuppressed with cyclosporine A, mycophenolate mofetil, and leflunomide remain normoglycemic for up to 100 days.	2001 Apr 27	11374396
Novel therapies in the treatment of systemic lupus erythematosus.	2001 Aug	11892912
Leflunomide Aventis Pharma.	2001 Feb	11816835
Radiography of rheumatoid arthritis in the time of increasing drug effectiveness.	2001 Feb	11177770
Newer immunomodulating drugs in rheumatoid arthritis may precipitate glomerulonephritis.	2001 Jan	11200876
Leflunomide inhibits activation of inducible nitric oxide synthase in rat astrocytes.	2001 Jan 19	11166726
Treatment of immune-mediated skin diseases: future perspectives.	2001 Jul-Aug	11399542
Conventional DMARD options for patients with a suboptimal response to methotrexate.	2001 Jun	11409154
Novel therapies for anti-neutrophil cytoplasmic antibody-associated vasculitis.	2001 Mar	11224696
Inhibition of cyclosporin-resistant B-cell antigen responses by pyrazoles: a tool for the identification of novel molecular mechanisms of B-cell activation.	2001 May	11377522
Which HAQ is best? A comparison of the HAQ, MHAQ and RA-HAQ, a difficult 8 item HAQ (DHAQ), and a rescored 20 item HAQ (HAQ20): analyses in 2,491 rheumatoid arthritis patients following leflunomide initiation.	2001 May	11361226
[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
Augmentation of apoptosis responses in p53-deficient L1210 cells by compounds directed at blocking NFkappaB activation.	2001 Nov-Dec	11911251
Current and emerging lupus treatments.	2001 Oct	11680781
Inhibition of HIV replication by A77 1726, the active metabolite of leflunomide, in combination with pyrimidine nucleoside reverse transcriptase inhibitors.	2001 Oct 1	11588518
Etanercept therapy for immune-mediated cochleovestibular disorders: preliminary results in a pilot study.	2001 Sep	11568668
Treating rheumatoid arthritis with new disease modifying drugs.	2002	11899752
Treatment of severe psoriasis and psoriatic arthritis with leflunomide.	2002 Feb	11903256
Experiences with leflunomide in solid organ transplantation.	2002 Feb 15	11884931
Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis.	2015 May 18	25811541

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.

Name

Type

Language

TERIFLUNOMIDE

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

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