Teriflunomide

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Teriflunomide
Teriflunomide structure.svg
Systematic (IUPAC) name
(2Z)-2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]but-2-enamide
Clinical data
Trade namesAubagio
Licence dataUS FDA:link
Pregnancy cat.X (US)
Legal status-only (US)
RoutesOral
Pharmacokinetic data
Protein binding>99.3%
Half-life2 weeks
ExcretionBiliary/fecal, renal
Identifiers
CAS number163451-81-8 N
ATC codeL04AA31
PubChemCID 5479847
ChemSpider16737143 YesY
UNII1C058IKG3B YesY
KEGGD10172 N
ChEBICHEBI:68540 N
ChEMBLCHEMBL973 YesY
Chemical data
FormulaC12H9F3N2O2 
Mol. mass270.207 g/mol
 N (what is this?)  (verify)
 
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Teriflunomide
Teriflunomide structure.svg
Systematic (IUPAC) name
(2Z)-2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]but-2-enamide
Clinical data
Trade namesAubagio
Licence dataUS FDA:link
Pregnancy cat.X (US)
Legal status-only (US)
RoutesOral
Pharmacokinetic data
Protein binding>99.3%
Half-life2 weeks
ExcretionBiliary/fecal, renal
Identifiers
CAS number163451-81-8 N
ATC codeL04AA31
PubChemCID 5479847
ChemSpider16737143 YesY
UNII1C058IKG3B YesY
KEGGD10172 N
ChEBICHEBI:68540 N
ChEMBLCHEMBL973 YesY
Chemical data
FormulaC12H9F3N2O2 
Mol. mass270.207 g/mol
 N (what is this?)  (verify)

Teriflunomide (trade name Aubagio, marketed by Sanofi, also known as A77 1726) 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[edit]

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[edit]

Leflunomide.svgE-Teriflunomide structure.svgTeriflunomide structure.svg

The structure which results from ring opening 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.

Space filling model of the E isomer of teriflunomide


See also[edit]

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

References[edit]

  1. ^ Magne D, Mézin F, Palmer G, Guerne PA (2006). "The active metabolite of leflunomide, A77 1726, increases proliferation of human synovial fibroblasts in presence of IL-1beta and TNF-alpha". Inflamm. Res. 55 (11): 469–75. doi:10.1007/s00011-006-5196-x. PMID 17122964. 
  2. ^ ClinicalTrials.gov Phase III Study of Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients With Multiple Sclerosis (TEMSO)
  3. ^ "Sanofi-Aventis’ Teriflunomide Comes Up Trumps in Two-Year Phase III MS Trial". 15 Oct 2010. 
  4. ^ Gever, John (June 4, 2012). "Teriflunomide Modest Help but Safe for MS". medpage. Joint meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis. report author= Vermersch, Pstrick. Retrieved June 4, 2012. 
  5. ^ "FDA approves new multiple sclerosis treatment Aubagio" (Press release). US FDA. Retrieved 2012-09-14. 
  6. ^ EU authorisation details, EMA, retrieved 2014-04-29 
  7. ^ H. Spreitzer (March 13, 2006). "Neue Wirkstoffe - Teriflunomid". Österreichische Apothekerzeitung (in German) (6/2006). 
  8. ^ Dr. Timothy Vollmer (May 28, 2009). "MS Therapies in the Pipeline: Teriflunomide". EMS News (May 28, 2009). 
  9. ^ Breedveld, FC; Dayer, J-M (November 2000). "Leflunomide: mode of action in the treatment of rheumatoid arthritis". Ann Rheum Dis 59 (11): 841–849. doi:10.1136/ard.59.11.841. PMC 1753034. PMID 11053058. 

External links[edit]