Teriflunomide

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Teriflunomide
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
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]

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.[6]

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.[7]

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.[8]

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. Retrieved June 04, 2012.  Unknown parameter |source= ignored (help)
  5. ^ "FDA approves new multiple sclerosis treatment Aubagio" (Press release). US FDA. Retrieved 2012-09-14. 
  6. ^ H. Spreitzer (March 13, 2006). "Neue Wirkstoffe - Teriflunomid". Österreichische Apothekerzeitung (in German) (6/2006). 
  7. ^ Dr. Timothy Vollmer (May 28, 2009). "MS Therapies in the Pipeline: Teriflunomide". EMS News (in English) (May 28, 2009). 
  8. ^ 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]