(2S)-2-[(4-{[(2,4-diaminopteridin-6-yl)methyl](methyl)amino}phenyl)formamido]pentanedioic acid

• ChemBase ID: 445
• Molecular Formular: C20H22N8O5
• Molecular Mass: 454.43928
• Monoisotopic Mass: 454.17131584
• SMILES: OC(=O)[C@@H](NC(=O)c1ccc(N(Cc2nc3c(nc2)nc(nc3N)N)C)cc1)CCC(=O)O
• Canonical SMILES: OC(=O)CC[C@@H](C(=O)O)NC(=O)c1ccc(cc1)N(Cc1cnc2c(n1)c(N)nc(n2)N)C
• InChI: InChI=1S/C20H22N8O5/c1-28(9-11-8-23-17-15(24-11)16(21)26-20(22)27-17)12-4-2-10(3-5-12)18(31)25-13(19(32)33)6-7-14(29)30/h2-5,8,13H,6-7,9H2,1H3,(H,25,31)(H,29,30)(H,32,33)(H4,21,22,23,26,27)/t13-/m0/s1
• InChIKey: FBOZXECLQNJBKD-ZDUSSCGKSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: (2S)-2-[(4-{[(2,4-diaminopteridin-6-yl)methyl](methyl)amino}phenyl)formamido]pentanedioic acid
• IUPAC Traditional name: methotrexate; (2S)-2-[(4-{[(2,4-diaminopteridin-6-yl)methyl](methyl)amino}phenyl)formamido]pentanedioic acid
• Brand Name: Abitrexate; Antifolan; Arbitrexate; Emtexate; Folex; Ledertrexate; Metatrexan; Methotrate; Mexate; Rheumatrex; Trexall
• Synonyms: N-[4-[[(2,4-Diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic Acid; (+)-Amethopterin; 4-Amino-N10-methylpteroylglutamic Acid; 4-Amino-N10-methylfolic Acid; Antifolan; CL 14377; EMT 25299; Emtexate; Ledertrexate; L-Metatrexan; Mexate; NSC 740; R 9985; MTX; N-Bismethylpteroylglutamic Acid; Methylaminopterinum; Methylaminopterin; Methotrexate Sodium; Amethopterin; Amethopterine; HDMTX; L-Amethopterin; Methopterin; Methotextrate; Methotrexat; Methotrexate; Methotrexate; Rheumatrex; Trexall; Abitrexate(Methotrexate); (S)-2-(4-(((2,4-Diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)pentanedioic acid; Extexate; Maxtrex; Methotrexate; (2S)-2-[(4-{[(2,4-diaminopteridin-6-yl)methyl](methyl)amino}phenyl)formamido]pentanedioic acid

Database IDs

• CAS Number: 59-05-2
• MDL Number: MFCD00064370; MFCD00150847
• PubChem SID: 160963908; 46507678
• PubChem CID: 126941
• CHEBI ID: 44185
• ATC CODE: L01BA01; L04AX03
• CHEMBL: 34259
• Chemspider ID: 112728
• DrugBank ID: DB00563
• KEGG ID: D00142
• Unique Ingredient Identifier: YL5FZ2Y5U1
• Wikipedia Title: Methotrexate
• Medline Plus: a682019

CALCULATED PROPERTIES

JChem

• Acid pKa: 3.2608347
• H Acceptors: 12
• H Donor: 5
• LogD (pH = 5.5): -3.6408224
• LogD (pH = 7.4): -6.5636883
• Log P: -0.23645228
• Molar Refractivity: 119.2108 cm^3
• Polarizability: 43.521362 Å^3
• Polar Surface Area: 210.54 Å^2
• Rotatable Bonds: 9
• Lipinski's Rule of Five: false

ALOGPS 2.1

• Log P: -0.91
• LOG S: -3.42
• Solubility (Water): 1.71e-01 g/l

PROPERTIES

Physical Property

• Solubility: 2600 mg/L; DMSO
• Apperance: Yellow Solid
• Melting Point: >188°C (dec.); 195 - 197°C
• Hydrophobicity(logP): -1.427; -2.2

Safety Information

• Storage Condition: -20°C; Refrigerator
• Storage Warning: Hygroscopic

Pharmacology Properties

• Target: Antimetabolite
• Admin Routes: oral, IV, IM, SC, intrathecal
• Bioavailability: 17–90%
• Excretion: renal 48–100%
• Half Life: 15 hours (dose dependent)
• Metabolism: hepatic
• Legal Status: POM (UK); Rx-only (US); S4 (Australia)
• Pregnancy Category: D (Australia); X (US)
• Mechanism of Action: Dihydrofolate reductase inhibitor

Product Information

• Purity: 95%; 95+%; 98%
• Salt Data: Free Base
• Application(s): Antineoplastic and antipsoriatic agent; Used in the treatment of rheumatoid arthritis.

DETAILS

DrugBank - DB00563

• Drug Groups: approved
• Description: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [PubChem]
• Indication: For the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole. Also for the treatment of severe psoriasis and severe, active, classical or definite rheumatoid arthritis.
• Pharmacology: Methotrexate is an antineoplastic anti-metabolite. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Methotrexate inhibits folic acid reductase which is responsible for the conversion of folic acid to tetrahydrofolic acid. At two stages in the biosynthesis of purines and at one stage in the synthesis of pyrimidines, one-carbon transfer reactions occur which require specific coenzymes synthesized in the cell from tetrahydrofolic acid. Tetrahydrofolic acid itself is synthesized in the cell from folic acid with the help of an enzyme, folic acid reductase. Methotrexate looks a lot like folic acid to the enzyme, so it binds to it quite strongly and inhibits the enzyme. Thus, DNA synthesis cannot proceed because the coenzymes needed for one-carbon transfer reactions are not produced from tetrahydrofolic acid because there is no tetrahydrofolic acid. Methotrexate selectively affects the most rapidly dividing cells (neoplastic and psoriatic cells). Methotrexate is also indicated in the management of severe, active, classical, or definite rheumatoid arthritis.
• Toxicity: Symptoms of overdose include bone marrow suppression and gastrointestinal toxicity. LD₅₀=43mg/kg(orally in rat).
• Affected Organisms: Humans and other mammals
• Biotransformation: Hepatic.
• Absorption: Generally well absorbed with a mean bioavailability of about 60%.
• Half Life: Low doses: 3 to 10 hours; High doses: 8 to 15 hours.
• Protein Binding: 50%, primarily to albumin
• Elimination: With IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose.
• Distribution: * 0.4 to 0.8 L/kg
• References: Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, Martin Mola E, Pavelka K, Sany J, Settas L, Wajdula J, Pedersen R, Fatenejad S, Sanda M: Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet. 2004 Feb 28;363(9410):675-81. [Pubmed] ; Johnston A, Gudjonsson JE, Sigmundsdottir H, Ludviksson BR, Valdimarsson H: The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules. Clin Immunol. 2005 Feb;114(2):154-63. [Pubmed]
• External Links: Wikipedia; RxList; PDRhealth; Drugs.com

Selleck Chemicals - S1210

Research Area: Immunology
Biological Activity:
Abitrexate(Methotrexate) is an antimetabolite and antifolate agent with antineoplastic and immunosuppressant activities. Methotrexate competitively and irreversibly inhibits dihydrofolate reductase (DHFR), resulting in inhibition of purine nucleotide and thymidylate synthesis and, subsequently, inhibition of DNA and RNA syntheses. Methotrexate also exhibits potent immunosuppressant activity although the mechanism(s) of actions is unclear. [1,2] In a panel of six pediatric leukemia and lymphoma cell lines, this drug performed growth inhibitory activity with median IC50 78 nM. [3]

Toronto Research Chemicals - M260675

A Folic acid antagonist. Used as a antineoplastic and antirheumatic.

REFERENCES

• Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, Martin Mola E, Pavelka K, Sany J, Settas L, Wajdula J, Pedersen R, Fatenejad S, Sanda M: Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet. 2004 Feb 28;363(9410):675-81. Pubmed
• Johnston A, Gudjonsson JE, Sigmundsdottir H, Ludviksson BR, Valdimarsson H: The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules. Clin Immunol. 2005 Feb;114(2):154-63. Pubmed
• http://en.wikipedia.org/wiki/Methotrexate
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