Identification
- Generic Name
- Aminopterin
- DrugBank Accession Number
- DB08878
- Background
Aminopterin is an amino derivative of folic acid, which was once used as an antineoplastic agent in the treatment of pediatric leukemia. In the 1950's its production was discontinued in favor of methotrexate, which is less potent but less toxic. Off label, aminopterin has also been used in the treatment of psoriasis. Clinicians need to be aware of the characteristic teratologic effects of aminopterin and methotrexate.
- Type
- Small Molecule
- Groups
- Investigational, Withdrawn
- Structure
Structure for Aminopterin (DB08878)
- Weight
- Average: 440.4127
Monoisotopic: 440.15566579 - Chemical Formula
- C19H20N8O5
- Synonyms
- 4-amino-4-deoxypteroylglutamate
- 4-amino-PGA
- 4-aminofolic acid
- 4-aminopteroylglutamic acid
- Aminopteridine
- Aminopterine
- APGA
- Minopterin
- N-(4-(((2,4-diamino-6-pteridinyl)methyl)amino)benzoyl)-L-glutamic acid
- Pteramina
- External IDs
- NSC-739
Pharmacology
- Indication
Prior to its withdrawal, aminopterin was initially used in the treatment of childhood leukemia; specifically to induce remissions. Later, aminopterin was used off-label in the United States to treat psoriasis, yielding dramatic lesion clearing. Aminopterin was later supplanted by methotrexate for treating cancer because of its better therapeutic index. Aminopterin (as well as methotrexate) has also been explored for use as an abortifacient. However, their association with severe congenital malformations and teratogenic effects have become known as fetal aminopterin syndrome.
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Avoid life-threatening adverse drug eventsImprove clinical decision support with information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events & improve clinical decision support.- Pharmacodynamics
Not Available
- Mechanism of action
Aminopterin is an amino derivative of folic acid which binds competitively to the dihydrofolate reductase enzyme to block tetrahydrofolate synthesis. Tetrahydrofolate is essential in the production of purines and pyrimadines, thus it's deficiency results in a reduction of DNA, RNA and protein synthesis.
- Absorption
Not Available
- Volume of distribution
Not Available
- Protein binding
Not Available
- Metabolism
- Not Available
- Route of elimination
Not Available
- Half-life
Not Available
- Clearance
Not Available
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Not Available
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAcetazolamide The therapeutic efficacy of Aminopterin can be increased when used in combination with Acetazolamide. Folic acid The therapeutic efficacy of Aminopterin can be decreased when used in combination with Folic acid. Leucovorin The therapeutic efficacy of Aminopterin can be decreased when used in combination with Leucovorin. Levoleucovorin The therapeutic efficacy of Aminopterin can be decreased when used in combination with Levoleucovorin. 
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- Not Available
Categories
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as folic acids. These are heterocyclic compounds based on the 4-[(pteridin-6-ylmethyl)amino]benzoic acid skeleton conjugated with one or more L-glutamate units.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Pteridines and derivatives
- Sub Class
- Pterins and derivatives
- Direct Parent
- Folic acids
- Alternative Parents
- Glutamic acid and derivatives / Hippuric acids / N-acyl-alpha amino acids / Aminobenzamides / Aniline and substituted anilines / Benzoyl derivatives / Phenylalkylamines / Secondary alkylarylamines / Aminopyrimidines and derivatives / Imidolactams show 12 more
- Substituents
- Alpha-amino acid or derivatives / Amine / Amino acid / Amino acid or derivatives / Aminobenzamide / Aminobenzoic acid or derivatives / Aminopyrimidine / Aniline or substituted anilines / Aralkylamine / Aromatic heteropolycyclic compound show 33 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- dicarboxylic acid (CHEBI:22526)
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- JYB41CTM2Q
- CAS number
- 54-62-6
- InChI Key
- TVZGACDUOSZQKY-LBPRGKRZSA-N
- InChI
- InChI=1S/C19H20N8O5/c20-15-14-16(27-19(21)26-15)23-8-11(24-14)7-22-10-3-1-9(2-4-10)17(30)25-12(18(31)32)5-6-13(28)29/h1-4,8,12,22H,5-7H2,(H,25,30)(H,28,29)(H,31,32)(H4,20,21,23,26,27)/t12-/m0/s1
- IUPAC Name
- (2S)-2-[(4-{[(2,4-diaminopteridin-6-yl)methyl]amino}phenyl)formamido]pentanedioic acid
- SMILES
- NC1=NC2=C(N=C(CNC3=CC=C(C=C3)C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=N2)C(N)=N1
References
- Synthesis Reference
http://www.sigmaaldrich.com/catalog/papers/16078850
- General References
- Aftimos S: Fetal methotrexate/aminopterin syndrome in an adult: a likely case with ectodermal abnormalities. Clin Dysmorphol. 2009 Jan;18(1):53-5. doi: 10.1097/MCD.0b013e32831552c4. [Article]
- Wheeler M, O'Meara P, Stanford M: Fetal methotrexate and misoprostol exposure: the past revisited. Teratology. 2002 Aug;66(2):73-6. [Article]
- NICHOL CA, WELCH AD: On the mechanism of action of aminopterin. Proc Soc Exp Biol Med. 1950 Jun;74(2):403-11. [Article]
- Menter A, Thrash B, Cherian C, Matherly LH, Wang L, Gangjee A, Morgan JR, Maeda DY, Schuler AD, Kahn SJ, Zebala JA: Intestinal transport of aminopterin enantiomers in dogs and humans with psoriasis is stereoselective: evidence for a mechanism involving the proton-coupled folate transporter. J Pharmacol Exp Ther. 2012 Sep;342(3):696-708. doi: 10.1124/jpet.112.195479. Epub 2012 May 31. [Article]
- Cole PD, Drachtman RA, Smith AK, Cate S, Larson RA, Hawkins DS, Holcenberg J, Kelly K, Kamen BA: Phase II trial of oral aminopterin for adults and children with refractory acute leukemia. Clin Cancer Res. 2005 Nov 15;11(22):8089-96. [Article]
- External Links
- KEGG Drug
- D02527
- PubChem Compound
- 169371
- PubChem Substance
- 175427130
- ChemSpider
- 148126
- BindingDB
- 50367055
- 1440264
- ChEBI
- 22526
- ChEMBL
- CHEMBL376180
- ZINC
- ZINC000002036915
- PDBe Ligand
- 04J
- Wikipedia
- Aminopterin
- PDB Entries
- 4kn1 / 4ky4
- MSDS
- Download (42.3 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 2 Completed Treatment Acute Lymphoblastic Leukemia (ALL) 1 2 Completed Treatment Leukemias 1 2 Completed Treatment Psoriasis (PsO) 1 2 Completed Treatment Rheumatoid Arthritis 1 2 Withdrawn Treatment Endometrial Cancer 1 1 Completed Treatment Psoriasis (PsO) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
- Not Available
- Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 225 °C (437 °F) MSDS water solubility 3.0X103 mg/L Not Available logP -1.8 HSDB pKa 5.5 HSDB - Predicted Properties
Property Value Source Water Solubility 0.106 mg/mL ALOGPS logP -0.25 ALOGPS logP -0.95 Chemaxon logS -3.6 ALOGPS pKa (Strongest Acidic) 3.38 Chemaxon pKa (Strongest Basic) 2.25 Chemaxon Physiological Charge -2 Chemaxon Hydrogen Acceptor Count 12 Chemaxon Hydrogen Donor Count 6 Chemaxon Polar Surface Area 219.33 Å2 Chemaxon Rotatable Bond Count 9 Chemaxon Refractivity 114.98 m3·mol-1 Chemaxon Polarizability 44.14 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.8035 Blood Brain Barrier + 0.6168 Caco-2 permeable - 0.7805 P-glycoprotein substrate Substrate 0.6625 P-glycoprotein inhibitor I Non-inhibitor 0.9325 P-glycoprotein inhibitor II Non-inhibitor 0.991 Renal organic cation transporter Non-inhibitor 0.894 CYP450 2C9 substrate Non-substrate 0.8749 CYP450 2D6 substrate Non-substrate 0.8116 CYP450 3A4 substrate Non-substrate 0.6336 CYP450 1A2 substrate Non-inhibitor 0.9188 CYP450 2C9 inhibitor Non-inhibitor 0.9199 CYP450 2D6 inhibitor Non-inhibitor 0.933 CYP450 2C19 inhibitor Non-inhibitor 0.9382 CYP450 3A4 inhibitor Non-inhibitor 0.8309 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9707 Ames test Non AMES toxic 0.9016 Carcinogenicity Non-carcinogens 0.9506 Biodegradation Not ready biodegradable 0.8542 Rat acute toxicity 2.6501 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9719 hERG inhibition (predictor II) Non-inhibitor 0.7778
Spectra
- Mass Spec (NIST)
- Download (20.5 KB)
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Nadph binding
- Specific Function
- Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA pre...
- Gene Name
- DHFR
- Uniprot ID
- P00374
- Uniprot Name
- Dihydrofolate reductase
- Molecular Weight
- 21452.61 Da
References
- Cocco L, Groff JP, Temple C Jr, Montgomery JA, London RE, Matwiyoff NA, Blakley RL: Carbon-13 nuclear magnetic resonance study of protonation of methotrexate and aminopterin bound to dihydrofolate reductase. Biochemistry. 1981 Jul 7;20(14):3972-8. [Article]
- Jackson RC, Niethammer D, Hart LI: Reactivation of dihydrofolate reductase inhibted by methotrexate or aminopterin. Arch Biochem Biophys. 1977 Aug;182(2):646-56. [Article]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- General Function
- Methotrexate transporter activity
- Specific Function
- Has been shown to act both as an intestinal proton-coupled high-affinity folate transporter and as an intestinal heme transporter which mediates heme uptake from the gut lumen into duodenal epithel...
- Gene Name
- SLC46A1
- Uniprot ID
- Q96NT5
- Uniprot Name
- Proton-coupled folate transporter
- Molecular Weight
- 49770.04 Da
References
- Menter A, Thrash B, Cherian C, Matherly LH, Wang L, Gangjee A, Morgan JR, Maeda DY, Schuler AD, Kahn SJ, Zebala JA: Intestinal transport of aminopterin enantiomers in dogs and humans with psoriasis is stereoselective: evidence for a mechanism involving the proton-coupled folate transporter. J Pharmacol Exp Ther. 2012 Sep;342(3):696-708. doi: 10.1124/jpet.112.195479. Epub 2012 May 31. [Article]
Drug created at May 14, 2013 19:45 / Updated at June 12, 2020 16:52