5-methyl-N-[4-(trifluoromethyl)phenyl]-1,2-oxazole-4-carboxamide

• ChemBase ID: 968
• Molecular Formular: C12H9F3N2O2
• Molecular Mass: 270.2072696
• Monoisotopic Mass: 270.0616122
• SMILES: FC(F)(F)c1ccc(NC(=O)c2c(onc2)C)cc1
• Canonical SMILES: O=C(c1cnoc1C)Nc1ccc(cc1)C(F)(F)F
• InChI: InChI=1S/C12H9F3N2O2/c1-7-10(6-16-19-7)11(18)17-9-4-2-8(3-5-9)12(13,14)15/h2-6H,1H3,(H,17,18)
• InChIKey: VHOGYURTWQBHIL-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 5-methyl-N-[4-(trifluoromethyl)phenyl]-1,2-oxazole-4-carboxamide
• IUPAC Traditional name: leflunomide; 5-methyl-N-[4-(trifluoromethyl)phenyl]-1,2-oxazole-4-carboxamide
• Brand Name: Arava
• Synonyms: Leflunomidum [INN-Latin]; Lefunomide [INN-Spanish]; leflunomide; Leflunomide; 5-Methylisoxazole-4-[4-trifluoromethylcarboxanilide]; Leflunomida; 5-Methyl-N-[4-(trifluoromethyl)phenyl]-4-isoxazolecarboxamide; Leflunomidum; 5-methyl-N-[4-(trifluoromethyl)phenyl]-1,2-oxazole-4-carboxamide; 5-Methylisoxazole-4-(4-trifluoromethyl)carboxanilide; Leflunomide; Arava

Database IDs

• CAS Number: 75706-12-6
• MDL Number: MFCD00867593
• PubChem SID: 160964431; 46506013; 24278516
• PubChem CID: 3899

CALCULATED PROPERTIES

JChem

• Acid pKa: 10.412348
• H Acceptors: 2
• H Donor: 1
• LogD (pH = 5.5): 2.5070803
• LogD (pH = 7.4): 2.506685
• Log P: 2.5070858
• Molar Refractivity: 64.1569 cm^3
• Polarizability: 21.993195 Å^3
• Polar Surface Area: 55.13 Å^2
• Rotatable Bonds: 3
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 2.52
• LOG S: -3.51
• Solubility (Water): 8.44e-02 g/l

PROPERTIES

Physical Property

• Solubility: 21 mg/L (poorly soluble); Dichloromethane; DMSO; Ether; Ethyl Acetate; Methanol
• Apperance: Off White Solid
• Melting Point: 153-156°C
• Hydrophobicity(logP): 2.324; 2.8

Safety Information

• Storage Condition: -20°C; -20°C Freezer
• RTECS: NY2354200
• European Hazard Symbols: Harmful (Xn)
• UN Number: 2811
• German water hazard class: 3
• Hazard Class: 6.1
• Packing Group: 3
• Risk Statements: 22-36/37/38
• Safety Statements: 26
• GHS Pictograms: GHS06
• GHS Signal Word: Danger
• GHS Hazard statements: H301-H315-H319-H335
• GHS Precautionary statements: P261-P301 + P310-P305 + P351 + P338
• Personal Protective Equipment: dust mask type N95 (US), Eyeshields, Faceshields, Gloves
• RID/ADR: UN 2811 6.1/PG 3
• Storage Temperature: 2-8°C

Pharmacology Properties

• Gene Information: human ... DHODH(1723)

Product Information

• Purity: 95%
• Salt Data: Free Base
• Empirical Formula (Hill Notation): C12H9F3N2O2

DETAILS

DrugBank - DB01097

• Drug Groups: approved; investigational
• Description: Leflunomide is a pyrimidine synthesis inhibitor belonging to the DMARD (disease-modifying antirheumatic drug) class of drugs, which are chemically and pharmacologically very heterogeneous. Leflunomide was approved by FDA and in many other countries (e.g., Canada, Europe) in 1999.
• Indication: For the management of the signs and symptoms of active rheumatoid arthritis (RA) to improve physical function and to slow the progression of structural damage associated with the disease. Has also been used for the prevention of acute and chronic rejection in recipients of solid organ trasnplants and is designated by the FDA as an orphan drug for this use.
• Pharmacology: Leflunomide is a pyrimidine synthesis inhibitor indicated in adults for the treatment of active rheumatoid arthritis (RA). RA is an auto-immune disease characterized by high T-cell activity. T cells have two pathways to synthesize pyrimidines: the salvage pathways and the de novo synthesis. At rest, T lymphocytes meet their metabolic requirements by the salvage pathway. Activated lymphocytes need to expand their pyrimidine pool 7- to 8-fold, while the purine pool is expanded only 2- to 3-fold. To meet the need for more pyrimidines, activated T cells use the de novo pathway for pyrimidine synthesis. Therefore, activated T cells, which are dependent on de novo pyrimidine synthesis, will be more affected by leflunomide's inhibition of dihydroorotate dehydrogenase than other cell types that use the salvage pathway of pyrimidine synthesis.
• Toxicity: LD₅₀=100-250 mg/kg (acute oral toxicity)
• Affected Organisms: Humans and other mammals
• Biotransformation: Primarily hepatic. Leflunomide is converted to its active form following oral intake.
• Absorption: Well absorbed, peak plasma concentrations appear 6-12 hours after dosing
• Half Life: 2 weeks
• Protein Binding: >99.3%
• Elimination: The active metabolite is eliminated by further metabolism and subsequent renal excretion as well as by direct biliary excretion. In a 28 day study of drug elimination (n=3) using a single dose of radiolabeled compound, approximately 43% of the total radioactivity was eliminated in the urine and 48% was eliminated in the feces. It is not known whether leflunomide is excreted in human milk.; Many drugs are excreted in human milk, and there is a potential for serious adverse reactions in nursing infants from leflunomide.
• Distribution: * 0.13 L/kg
• References: Goldenberg MM: Leflunomide, a novel immunomodulator for the treatment of active rheumatoid arthritis. Clin Ther. 1999 Nov;21(11):1837-52; discussion 1821. [Pubmed] ; Li EK, Tam LS, Tomlinson B: Leflunomide in the treatment of rheumatoid arthritis. Clin Ther. 2004 Apr;26(4):447-59. [Pubmed] ; Sanders S, Harisdangkul V: Leflunomide for the treatment of rheumatoid arthritis and autoimmunity. Am J Med Sci. 2002 Apr;323(4):190-3. [Pubmed] ; Breedveld FC, Dayer JM: Leflunomide: mode of action in the treatment of rheumatoid arthritis. Ann Rheum Dis. 2000 Nov;59(11):841-9. \ [Pubmed] ; Reitzik M, Lownie JF: Familial polyostotic fibrous dysplasia. Oral Surg Oral Med Oral Pathol. 1975 Dec;40(6):769-74. [Pubmed] ; Herrmann ML, Schleyerbach R, Kirschbaum BJ: Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases. Immunopharmacology. 2000 May;47(2-3):273-89. [Pubmed] ; Schattenkirchner M: The use of leflunomide in the treatment of rheumatoid arthritis: an experimental and clinical review. Immunopharmacology. 2000 May;47(2-3):291-8. [Pubmed] ; Fox RI: Mechanism of action of leflunomide in rheumatoid arthritis. J Rheumatol Suppl. 1998 Jul;53:20-6. [Pubmed]
• External Links: Wikipedia; RxList; Drugs.com

Selleck Chemicals - S1247

Research Area: Anaplastic astrocytoma
Biological Activity:
Leflunomide is a pyrimidine synthesis inhibitor belonging to the DMARD (disease-modifying antirheumatic drug) class of drugs. Leflunomide is used to relieve symptoms caused by rheumatoid arthritis, such as inflammation, swelling, stiffness, and joint pain. This medicine works by stopping the body from producing too many of the immune cells that are responsible for the swelling and inflammation. [1]

Sigma Aldrich - L5025

Biochem/physiol Actions
Immunosuppressive; inhibits T and B cell proliferation. Activity is attributed mainly to its metabolite, a malononitrile derivative, which is believed to inhibit dihydroorotate dehydrogenase (in the de novo pyrimidine synthesis pathway) as well as several protein tyrosine kinases.
Application
By virtue of its immunosuppressant effects, leflunomide has found use in organ transplantation1 and treatment of rheumatoid arthritis2 and other autoimmune diseases.

Toronto Research Chemicals - L322750

An immunosuppressive. Inhibits T and B cell proliferation. Activity is attributed mainly to its metabolite, a malononitrile derivative, which is beleived to inhibit dihydroorotate dehydrogenase as well as several protein tyrosine kinases. Therapeutical

REFERENCES

• Goldenberg MM: Leflunomide, a novel immunomodulator for the treatment of active rheumatoid arthritis. Clin Ther. 1999 Nov;21(11):1837-52; discussion 1821. Pubmed
• Li EK, Tam LS, Tomlinson B: Leflunomide in the treatment of rheumatoid arthritis. Clin Ther. 2004 Apr;26(4):447-59. Pubmed
• Sanders S, Harisdangkul V: Leflunomide for the treatment of rheumatoid arthritis and autoimmunity. Am J Med Sci. 2002 Apr;323(4):190-3. Pubmed
• Breedveld FC, Dayer JM: Leflunomide: mode of action in the treatment of rheumatoid arthritis. Ann Rheum Dis. 2000 Nov;59(11):841-9. Pubmed\
• Reitzik M, Lownie JF: Familial polyostotic fibrous dysplasia. Oral Surg Oral Med Oral Pathol. 1975 Dec;40(6):769-74. Pubmed
• Herrmann ML, Schleyerbach R, Kirschbaum BJ: Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases. Immunopharmacology. 2000 May;47(2-3):273-89. Pubmed
• Schattenkirchner M: The use of leflunomide in the treatment of rheumatoid arthritis: an experimental and clinical review. Immunopharmacology. 2000 May;47(2-3):291-8. Pubmed
• Fox RI: Mechanism of action of leflunomide in rheumatoid arthritis. J Rheumatol Suppl. 1998 Jul;53:20-6. Pubmed
• www.mayoclinic.com/health/drug-information/DR60155
• Vrenken, T., et al.: J. Hepatol., 49, 799 (2008)
• Mazzucco, G., et al.: Clin. Nephrol., 70, 163 (2008)
• Davies, M., et al.: J. Med. Chem., 52, 2683 (2008)