Description
Teriflunomide (Aubagio®), also known as A77 1726, is an immunosupressant marketed by Sanofi for
the teatment of multiple sclerosis (MS). Teriflunomide is the active metabolite of leflunomide, used
for treatment of patients diagnosed with rheumatoid arthritis, and therefore simultaneously can be used
as a treatment for rheumatoid arthritis.Teriflunomide acts as an inhibitor of the mitochondrial
enzyme dihydrorotate dehydrogenase, inhibiting pyrimidine formation, and resulting in reduced
B and T cell proliferation.
Chemical Properties
White Solid
Uses
The active metabolite of Leflunomide, 2-Cyano-3-hydroxy-N-(4'-trifluoromethylphenyl)-crotone amide can be used as a potent disease-modifying antirheumatic drug used in the treatment of rheumatoid arthritis.
Definition
ChEBI: Teriflunomide is an enamide obtained by formal condensation of the carboxy group of (2Z)-2-cyano-3-hydroxybut-2-enoic acid with the anilino group of 4-(trifluoromethyl)aniline. Used for the treatment of relapsing forms of multiple sclerosis and rheumatoid arthritis. It has a role as an EC 1.3.98.1 [dihydroorotate oxidase (fumarate)] inhibitor, a tyrosine kinase inhibitor, a hepatotoxic agent, a drug metabolite and a non-steroidal anti-inflammatory drug. It is a nitrile, an enol, an aromatic amide, an enamide, a member of (trifluoromethyl)benzenes and a secondary carboxamide.
Clinical Use
Immunomodulating agent:
Treatment of relapsing remitting multiple sclerosis
Synthesis
Numerous syntheses of teriflunomide have been developed to date, most relying on the use of 4-
trifluoromethyl aniline (167). The current optimized method for scale-up synthesis of teriflunomide,
developed by Keshav and coworkers, begins with reaction of commercial 4-trifluoromethyl aniline 167
and ethylacetoacetate (168) in refluxing xylenes, providing acetoamidate 169 in 51% yield . The resulting acetoamidate 169 was then treated with H2O2, KBr, and concentrated HCl at room
temperature, providing bromide 170 in 67% yield. Bromide 170 was reacted with NaCN in DMSO,
generating teriflunomide (XXVI) in 85% yield.
Drug interactions
Potentially hazardous interactions with other drugs
Lipid-lowering agents: effect significantly reduced by
colestyramine - avoid; concentration of rosuvastatin
increased - consider reducing rosuvastatin dose.
Live vaccines: risk of generalised infections - avoid.
Metabolism
Teriflunomide is the active metabolite of leflunomide.
It is moderately metabolised and teriflunomide is
the only component detected in plasma. The main
biotransformation pathway is hydrolysis with oxidation
being a minor pathway. Secondary pathways involve
oxidation, N-acetylation and sulfate conjugation.
Teriflunomide is excreted in the gastrointestinal tract
mainly through the bile as unchanged drug and most
likely by direct secretion.
References
[1] S. MANNA B A. Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-kappa B activation and gene expression.[J]. Journal of immunology, 1999, 162 4 1: 2095-2102. DOI:
10.4049/jimmunol.162.4.2095[2] JUNE P. DAVIS. The Immunosuppressive Metabolite of Leflunomide Is a Potent Inhibitor of Human Dihydroorotate Dehydrogenase[J]. Biochemistry Biochemistry, 1996, 35 4: 1270-1273. DOI:
10.1021/bi952168g[3] QUEE MING SEAH. Oxidative bioactivation and toxicity of leflunomide in immortalized human hepatocytes and kinetics of the non-enzymatic conversion to its major metabolite, A77 1726.[J]. Drug metabolism letters, 2008, 2 3: 153-157. DOI:
10.2174/187231208785425791
