163451-81-8

Basic information

• Product Name: A77 1726
• Synonyms: A77 1726 (Teriflunomide);LeflunoMide EP IMpurity B;A 1726;Flucyamide;HMR 1726;(Z)-2-Cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide
• CAS NO: 163451-81-8
• Molecular Formula: C12H9F3N2O2
• Molecular Weight: 270.2072696
• EINECS: 1308068-626-2
• Product Categories: Metabolites & Impurities;Tyrosine Kinase Inhibitors
• Mol File: 163451-81-8.mol
• Article Data: 25

Chemical Properties

• Melting Point: 229-232°C
• Boiling Point: 410.8 °C at 760 mmHg
• Flash Point: 202.3 °C
• Appearance: white to beige/
• Density: 1.424 g/cm³
• Vapor Pressure: 6.63E-06mmHg at 25°C
• Refractive Index: 1.551
• Storage Temp.: Hygroscopic, -20°C Freezer, Under Inert Atmosphere
• Solubility: DMSO: soluble5mg/mL, clear (warmed)
• PKA: 5.20±0.50(Predicted)
• Merck: 14,9165
• CAS DataBase Reference: A77 1726(CAS DataBase Reference)
• NIST Chemistry Reference: A77 1726(163451-81-8)
• EPA Substance Registry System: A77 1726(163451-81-8)

Safety Data

• Hazard Codes: Xn
• Statements: 22
• WGK Germany: 3
• Hazardous Substances Data: 163451-81-8(Hazardous Substances Data)

Usage

Description

Different sources of media describe the Description of 163451-81-8 differently. You can refer to the following data:
1. 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.
2. 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

Different sources of media describe the Uses of 163451-81-8 differently. You can refer to the following data:
1. Teriflunomide has been used as a dihydroorotate dehydrogenase (DHODH) inhibitor.
2. 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.
3. 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.

InChI:InChI=1/C12H9F3N2O2/c1-7(18)10(6-16)11(19)17-9-4-2-8(3-5-9)12(13,14)15/h2-5,17,19H,1H3/b11-10-

Upstream product

• 75706-12-6 Leflunomide 
• 773837-37-9 sodium cyanide 
• 1206724-43-7 2-bromo-3-oxo-N-[4-(trifluoromethyl)phenyl]butanamide 
• 42831-50-5 5-methyl-1,2-oxazole-4-carboxylic acid 
• 24522-30-3 2-cyano-N-(4-trifluoromethylphenyl)acetamide 
• 75-36-5 acetyl chloride 
• 75706-11-5 2-ethoxymethyleneacetoacetyl-(4-trifluoromethyl)aniline 
• 351-87-1 N-(4-trifluoromethylphenyl)-2-acetylacetamide 
• 455-14-1 4-trifluoromethylphenylamine 
• 108-24-7 acetic anhydride 
• 7647-01-0 hydrogenchloride 
• 87853-82-5 ethyl 2-cyano-3-hydroxybut-2-enoate 

Downstream Products

• 695191-69-6 5-amino-3-methyl-isoxazole-4-carboxylic acid (4-trifluoromethyl-phenyl)-amide 

Relevant articles and documents

Simple preparation method of teriflunomide

The invention provides a simple preparation method of teriflunomide, and belongs to the field of medicinal chemistry. The preparation method comprises the following steps of: (1) mixing 5-methylisoxazole-4-formic acid and a condensing agent in a solvent under an alkaline condition, and carrying out condensation reaction to obtain an active ester system; (2) mixing the active ester system and 4-trifluoromethylaniline in a solvent, and carrying out condensation reaction to obtain an intermediate leflunomide; and (3) carrying out alkali treatment and acid treatment on the obtained intermediate leflunomide to obtain teriflunomide. According to the method, the 5-methylisoxazole-4-formic acid reacts with the 4-trifluoromethylaniline in the form of active ester, so that the reaction activity of the 5-methylisoxazole-4-formic acid and the 4-trifluoromethylaniline is improved, the reaction condition is mild, the obtained intermediate leflunomide does not need to be purified, and the yield of teriflunomide is improved.

Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function

Ion selectivity is a defining feature of a given ion channel and is considered immutable. Here we show that ion selectivity of the lysosomal ion channel TPC2, which is hotly debated (Calcraft et al., 2009; Guo et al., 2017; Jha et al., 2014; Ruas et al., 2015; Wang et al., 2012), depends on the activating ligand. A high-throughput screen identified two structurally distinct TPC2 agonists. One of these evoked robust Ca2+-signals and non-selective cation currents, the other weaker Ca2+-signals and Na+-selective currents. These properties were mirrored by the Ca2+- mobilizing messenger, NAADP and the phosphoinositide, PI(3,5)P2, respectively. Agonist action was differentially inhibited by mutation of a single TPC2 residue and coupled to opposing changes in lysosomal pH and exocytosis. Our findings resolve conflicting reports on the permeability and gating properties of TPC2 and they establish a new paradigm whereby a single ion channel mediates distinct, functionally-relevant ionic signatures on demand.

Kemp Eliminases of the AlleyCat Family Possess High Substrate Promiscuity

Minimalist enzymes designed to catalyze model reactions provide useful starting points for creating catalysts for practically important chemical transformations. We have shown that Kemp eliminases of the AlleyCat family facilitate conversion of leflunomid