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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 of TERIFLUNOMIDE

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
Defined Stereocenters 0 / 0
E/Z Centers 1
Optical Activity NONE

Description

Leflunomide is a pyrimidine synthesis inhibitor belonging to the DMARD (disease-modifying antirheumatic drug) class of drugs, which are chemically and pharmacologically very heterogeneous. Leflunomide was approved by FDA and in many other countries. Leflunomide is an isoxazole immunomodulatory agent that inhibits dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect. Leflunomide is rapidly metabolized to its active form, teriflunomide (A77 1726). Two mechanisms of action have been identified for A77 1726: inhibition of dihydroorotate dehydrogenase (DHODH) and inhibition of tyrosine kinases. DHODH inhibition occurs at lower concentrations of A77 1726 than that of tyrosine kinases and is currently considered the major mode of action. Human dihydroorotate dehydrogenase consists of 2 domains: an α/β-barrel domain containing the active site and an α-helical domain that forms a tunnel leading to the active site. A77 1726 binds to the hydrophobic tunnel at a site near the flavin mononucleotide. Inhibition of dihydroorotate dehydrogenase by A77 1726 prevents production of rUMP by the de novo pathway; such inhibition leads to decreased rUMP levels, decreased DNA and RNA synthesis, inhibition of cell proliferation, and G1 cell cycle arrest. It is through this action that leflunomide inhibits autoimmune T-cell proliferation and production of autoantibodies by B cells. Since salvage pathways are expected to sustain cells arrested in the G1 phase, the activity of leflunomide is cytostatic rather than cytotoxic. Tyrosine kinases activate signalling pathways leading to DNA repair, apoptosis and cell proliferation. Inhibition of tyrosine kinases can help to treating cancer by preventing repair of tumor cells. Teriflunomide is also an inhibitor of CYP2C8 in vivo. In patients taking leflunomide, exposure of drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide, rosiglitazone) may be increased. Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo. For a patient taking leflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. For other substrates of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate, rifampin), especially HMG-Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravastatin, repaglinide, and simvastatin), consider reducing the dose of these drugs and monitor patients closely for signs and symptoms of increased exposures to the drugs while patients are taking leflunomide.

CNS Activity

Originator

Approval Year

PubMed

PubMed

TitleDatePubMed
Structural and functional comparison of agents interfering with dihydroorotate, succinate and NADH oxidation of rat liver mitochondria.
1998 Oct 15
Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-kappa B activation and gene expression.
1999 Feb 15
Vasculitis occurring during leflunomide therapy.
2001
The heterotopic tracheal allograft as an animal model of obliterative bronchiolitis.
2001
A clinical and economic review of disease-modifying antirheumatic drugs.
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
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
Leflunomide-mediated suppression of antiviral antibody and Tcell responses: differential restoration by uridine.
2001 Aug 27
[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
[Application of leflunomide in the treatment of patients with rheumatoid arthritis].
2001 Feb
Discussion. Treatment algorithm: managing rheumatoid arthritis.
2001 Jul
Economic and quality-of-life impact of rheumatoid arthritis.
2001 Jul
Recombinant expression of N-terminal truncated mutants of the membrane bound mouse, rat and human flavoenzyme dihydroorotate dehydrogenase. A versatile tool to rate inhibitor effects?
2001 Mar
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
Inhibition of angiogenesis-related endothelial activity by the experimental immunosuppressive agent leflunomide.
2001 Nov 15
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
Current and emerging lupus treatments.
2001 Oct
Leflunomide for the treatment of systemic lupus erythematosus: comment on the article by McMurray.
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
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
[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
Economic comparison of leflunomide and methotrexate in patients with rheumatoid arthritis: an evaluation based on a 1-year randomised controlled trial.
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
A77 1726 induces differentiation of human myeloid leukemia K562 cells by depletion of intracellular CTP pools.
2002 Sep
[The active metabolite of leflunomide A771726 inhibits proliferation and collagen synthesis of hepatic stellate cell].
2004 Nov
Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase.
2007 Jan 25
The immunomodulatory drug Leflunomide inhibits cell cycle progression of B-CLL cells.
2008 Mar
Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells.
2009 Feb
Hepatic cytochrome P450s attenuate the cytotoxicity induced by leflunomide and its active metabolite A77 1726 in primary cultured rat hepatocytes.
2011 Aug
Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis.
2015 May 18
Patents

Sample Use Guides

In Vivo Use Guide
7 mg or 14 mg orally once daily, with or without food
Route of Administration: Oral
Substance Class Chemical
Created
by admin
on Mon Oct 21 22:16:45 UTC 2019
Edited
by admin
on Mon Oct 21 22:16:45 UTC 2019
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
Classification Tree Code System Code
LIVERTOX 940
Created by admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
WHO-VATC QL04AA31
Created by admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
NCI_THESAURUS C471
Created by admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
EMA ASSESSMENT REPORTS AUBAGIO (AUTHORIZED: MULTIPLE SCLEROSIS)
Created by admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
NDF-RT N0000185502
Created by admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
WHO-ATC L04AA31
Created by admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
Code System Code Type Description
DRUG BANK
DB08880
Created by admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
PRIMARY
LactMed
163451-81-8
Created by admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
PRIMARY
PUBCHEM
54684141
Created by admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
PRIMARY
EVMPD
SUB25218
Created by admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
PRIMARY
MESH
C527525
Created by admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
PRIMARY
WIKIPEDIA
TERIFLUNOMIDE
Created by admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
PRIMARY
INN
7761
Created by admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
PRIMARY
NDF-RT
N0000185501
Created by admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
PRIMARY Dihydroorotate Dehydrogenase Inhibitors [MoA]
MERCK INDEX
M10578
Created by admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
PRIMARY Merck Index
ChEMBL
CHEMBL973
Created by admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
PRIMARY
CAS
108605-62-5
Created by admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
NON-SPECIFIC STEREOCHEMISTRY
NCI_THESAURUS
C76662
Created by admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
PRIMARY
IUPHAR
6844
Created by admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
PRIMARY
RXCUI
1310520
Created by admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
PRIMARY RxNorm
CAS
163451-81-8
Created by admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
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
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