A77 1726 Chemical Properties

Melting point:

229-232°C

Boiling point:

410.8±45.0 °C(Predicted)

Density 

1.424±0.06 g/cm3(Predicted)

storage temp. 

-20°C

solubility 

DMSO: soluble5mg/mL, clear (warmed)

pka

5.20±0.50(Predicted)

form 

powder

color 

white to beige

λmax

203nm(MeOH)(lit.)

Merck 

14,9165

Stability:

Hygroscopic

InChIKey

UTNUDOFZCWSZMS-YFHOEESVSA-N

Safety Information

Hazard Codes 

Xn

Risk Statements 

22

WGK Germany 

3

HS Code 

2926.90.4801

A77 1726 Usage And Synthesis

Description

In September 2012, the US FDA approved teriflunomide (also referred to as HMR-1726) as a therapy for patients with relapsing forms of multiple sclerosis (MS). Teriflunomide is the second approved oral treatment option for MS, after Gilenya? which was approved in 2010. Teriflunomide, which is the active metabolite of leflunomide (a marketed drug for the treatment of rheumatoid and psoriatic arthritis), is a non?competitive and selective inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme in the de novo synthesis of pyrimidines. Although the net effect of inhibition of DHODH by teriflunomide and its therapeutic effect in MS are not clear, it is hypothesized that by inhibiting de novo pyrimidine synthesis, the effector functions of activated lymphocytes are suppressed, thus dampening the effect of an overactive immune system.

Description

A-771726 is an active metabolite of the prodrug leflunomide that inhibits dihydroorotate dehydrogenase (DHODH; IC₅₀ = 0.23 μM). A-771726 inhibits the production of prostaglandin E₂ (PGE₂; ) in TNF-α- or IL-1α-stimulated isolated human synoviocytes (IC₅₀s = 7 and 3 μM, respectively). It inhibits the proliferation of isolated human peripheral blood mononuclear cells (PBMCs) when used at concentrations of 25 and 100 μM. A-771726 (3 and 10 mg/kg) delays disease onset and decreases neurological deficits in a rat model of experimental autoimmune encephalomyelitis (EAE) induced by complete Freund’s adjuvant (CFA) and M. tuberculosis. Formulations containing teriflunomide have been used in the treatment of multiple sclerosis.

Chemical Properties

White Solid

Originator

Genzyme (United States)

Uses

Teriflunomide has been used as a dihydroorotate dehydrogenase (DHODH) inhibitor.

Uses

The active metabolite of Leflunomide, a potent disease-modifying antirheumatic drug used in the treatment of rheumatoid arthritis. LEF-M interferes with dendritic cell function.

Uses

A-771726 is the active metabolite of leflunomide, a prodrug approved by the FDA for treatment of rheumatoid arthritis. A-771726 reversibly inhibits dihydroorotate dehydrogenase, the rate-limiting step in the de novo synthesis of pyrimidines. It prevents activated lymphocytes from accumulating sufficient pyrimidines to support DNA synthesis (IC50s = 0.09, 3.5, and 12.5 μM for rat, mouse, and human, respectively). At higher doses, A-771726 inhibits tyrosine kinases responsible for early T cell and B cell signaling in the G0/G1 phase of the cell cycle. A-771726 has also been shown to inhibit the production of prostaglandin E2 in synoviocytes activated by TNF-α and IL-1α (IC50s = 7 and 3 μM, respectively) as well as inhibit MMP-1 and IL-6 production at concentrations >10 μM.[Cayman Chemical]

Definition

ChEBI: 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.

brand name

Aubagio

General Description

Teriflunomide, marketed under the trade name Aubagio, is the active metabolite of leflunomide, an immunosuppressive disease-modifying antirheumatic drug, used in active moderate-to-severe rheumatoid arthritis and psoriatic arthritis. An analytical reference standard for use in LC/MS or GC/MS applications including clinical and diagnostic testing such as therapeutic drug monitoring assays.

Biochem/physiol Actions

Teriflunomide is an orally available anti-inflammatory immunomodulator. It blocks the activity of dihydroorotate dehydrogenase, preventing pyrimidine synthesis and T and B cell proliferation and function. Teriflunomide has been used to treat rheumatoid arthritis and was recently approved for multiple sclerosis.

References

[1] yao h w, li j, chen j q, et al. a 771726, the active metabolite of leflunomide, inhibits tnf-α and il-1 from kupffer cells[j]. inflammation, 2004, 28(2): 97-103.
[2] breedveld f c, dayer j m. leflunomide: mode of action in the treatment of rheumatoid arthritis[j]. annals of the rheumatic diseases, 2000, 59(11): 841-849.
[3] burger d, begué‐pastor n, benavent s, et al. the active metabolite of leflunomide, a77 1726, inhibits the production of prostaglandin e2, matrix metalloproteinase 1 and interleukin 6 in human fibroblast‐like synoviocytes[j]. rheumatology, 2003, 42(1): 89-96.
[4] davis j p, cain g a, pitts w j, et al. the immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase[j]. biochemistry, 1996, 35(4): 1270-1273.

A77 1726(163451-81-8)Related Product Information

• Teriflunomide-d4
• 5-DesMethyl-3-Methyl LeflunoMide
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• LeflunoMide EP IMpurity G
• 2-cyano-N-[4-(trifluoromethyl)phenyl]acetamide
• 5-Methyl-4-isoxazolecarboxylic acid
• LeflunoMide EP IMpurity F
• Leflunomide 3-Isomer
• LeflunoMide EP IMpurity E
• 4-Aminobenzotrifluoride
• Leflunomide