Teriflunomide

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Teriflunomide
Teriflunomide structure.svg
Ball-and-stick model of the teriflunomide molecule
Systematic (IUPAC) name
(2Z)-2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]but-2-enamide
Clinical data
Trade names Aubagio
Licence data US FDA:link
Pregnancy
category
  • US: X (Contraindicated)
Legal status
Routes of
administration
Oral (tablets)
Pharmacokinetic data
Protein binding >99.3%
Biological half-life 2 weeks
Excretion Biliary/fecal, renal
Identifiers
CAS Number 163451-81-8 N
ATC code L04AA31 (WHO)
PubChem CID: 54684141
IUPHAR/BPS 6844
ChemSpider 16737143 YesY
UNII 1C058IKG3B YesY
KEGG D10172 N
ChEBI CHEBI:68540 N
ChEMBL CHEMBL973 YesY
Synonyms A77 1726
Chemical data
Formula C12H9F3N2O2
Molecular mass 270.207 g/mol
  • O=C(Nc1ccc(cc1)C(F)(F)F)C(/C#N)=C(/C)O
  • 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- YesY
  • Key:UTNUDOFZCWSZMS-YFHOEESVSA-N YesY
 NYesY (what is this?)  (verify)

Teriflunomide (trade name Aubagio, marketed by Sanofi) is the active metabolite of leflunomide.[1] Teriflunomide was investigated in the Phase III clinical trial TEMSO as a medication for multiple sclerosis (MS). The study was completed in July 2010.[2] 2-year results were positive.[3] However, the subsequent TENERE head-to-head comparison trial reported that "although permanent discontinuations [of therapy] were substantially less common among MS patients who received teriflunomide compared with interferon beta-1a, relapses were more common with teriflunomide."[4] The drug was approved by the FDA on September 13, 2012[5] and in the European Union on August 26, 2013.[6]

Mechanisms of action

Teriflunomide is an immunomodulatory drug inhibiting pyrimidine de novo synthesis by blocking the enzyme dihydroorotate dehydrogenase. It is uncertain whether this explains its effect on MS lesions.[7]

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.[8]

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.[9]

Activation of leflunomide to teriflunomide

The branded drug teriflunomide is the main active in vivo metabolite of the generically available leflunomide. Upon administration of leflunomide, 70% of the drug administered converts into teriflunomide. The only difference between the molecules is the opening of the isoxazole ring. This is considered a simple structural modification and a technically simple one-step synthetic transformation. Upon oral administration of leflunomide in vivo, the isoxazole ring of leflunomide is opened and teriflunomide is formed.[10]

Teriflunomide is the only active metabolite of leflunomide, completely responsible for its therapeutic actions. It results from the reaction of isoxazole ring opening, which occurs in vivo. Teriflunomide then can interconvert between the E and Z enolic forms (and the corresponding keto-amide), the Z-enol being the most stable and therefore most predominant form.[11][12]

"Regardless of the substance administered (leflunomide or teriflunomide), it is the same molecule (teriflunomide)—the one exerting the pharmacological, immunological or metabolic action in view of restoring, correcting or modifying physiological functions, and does not present, in clinical use, a new chemical entity to patients."[10] Because of this, EMA initially had not considered teriflunomide being a new active substance.[13]

See also

See leflunomide for information on pharmacokinetics, side effects, contraindications and other data.

References

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  2. ClinicalTrials.gov Phase III Study of Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients With Multiple Sclerosis (TEMSO)
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External links