Identification

Name
Aminopterin
Accession Number
DB08878
Type
Small Molecule
Groups
Investigational, Withdrawn
Description

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.

Structure
Thumb
Synonyms
  • 4-amino-4-deoxypteroylglutamate
  • 4-amino-PGA
  • 4-aminofolic acid
  • 4-aminopteroylglutamic acid
  • 4'-Amino-folsaeure
  • A-ninopterin
  • A-Ninopterin
  • Aminopteridine
  • Aminopterine
  • APGA
  • Minopterin
  • N-(4-{[(2,4-Diamino-6-pteridinyl)methyl]amino}benzoyl)glutamic acid
  • Pteramina
External IDs
NSC-739
Categories
UNII
JYB41CTM2Q
CAS number
54-62-6
Weight
Average: 440.4127
Monoisotopic: 440.15566579
Chemical Formula
C19H20N8O5
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[[email protected]@H](CCC(O)=O)C(O)=O)C=N2)C(N)=N1

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.

Structured Indications
Not Available
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
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

Synthesis Reference

http://www.sigmaaldrich.com/catalog/papers/16078850

General References
  1. 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. [PubMed:19011571]
  2. Wheeler M, O'Meara P, Stanford M: Fetal methotrexate and misoprostol exposure: the past revisited. Teratology. 2002 Aug;66(2):73-6. [PubMed:12210010]
  3. NICHOL CA, WELCH AD: On the mechanism of action of aminopterin. Proc Soc Exp Biol Med. 1950 Jun;74(2):403-11. [PubMed:15440837]
  4. 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. [PubMed:22653877]
  5. 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. [PubMed:16299240]
External Links
KEGG Drug
D02527
PubChem Compound
169371
PubChem Substance
175427130
ChemSpider
148126
BindingDB
50367055
ChEBI
22526
ChEMBL
CHEMBL376180
HET
04J
Wikipedia
Aminopterin
PDB Entries
4kn1 / 4ky4
MSDS
Download (42.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentPsoriasis1
2CompletedTreatmentAcute Lymphocytic Leukemia (ALL)1
2CompletedTreatmentLeukemias1
2Unknown StatusTreatmentEndometrial Cancers1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)225 °C (437 °F)MSDS
water solubility3.0X103 mg/LNot Available
logP-1.8HSDB
pKa5.5HSDB
Predicted Properties
PropertyValueSource
Water Solubility0.106 mg/mLALOGPS
logP-0.25ALOGPS
logP-0.95ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)3.38ChemAxon
pKa (Strongest Basic)2.25ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count12ChemAxon
Hydrogen Donor Count6ChemAxon
Polar Surface Area219.33 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity114.98 m3·mol-1ChemAxon
Polarizability44.14 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.8035
Blood Brain Barrier+0.6168
Caco-2 permeable-0.7805
P-glycoprotein substrateSubstrate0.6625
P-glycoprotein inhibitor INon-inhibitor0.9325
P-glycoprotein inhibitor IINon-inhibitor0.991
Renal organic cation transporterNon-inhibitor0.894
CYP450 2C9 substrateNon-substrate0.8749
CYP450 2D6 substrateNon-substrate0.8116
CYP450 3A4 substrateNon-substrate0.6336
CYP450 1A2 substrateNon-inhibitor0.9188
CYP450 2C9 inhibitorNon-inhibitor0.9199
CYP450 2D6 inhibitorNon-inhibitor0.933
CYP450 2C19 inhibitorNon-inhibitor0.9382
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9707
Ames testNon AMES toxic0.9016
CarcinogenicityNon-carcinogens0.9506
BiodegradationNot ready biodegradable0.8542
Rat acute toxicity2.6501 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9719
hERG inhibition (predictor II)Non-inhibitor0.7778
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (20.5 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
Folic acid / Glutamic acid or derivatives / Hippuric acid or derivatives / Hippuric acid / N-acyl-alpha-amino acid / N-acyl-alpha amino acid or derivatives / Alpha-amino acid or derivatives / Aminobenzamide / Aminobenzoic acid or derivatives / Benzamide
show 33 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
dicarboxylic acid (CHEBI:22526)

Enzymes

Details
1. Dihydrofolate reductase
Kind
Protein
Organism
Human
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
  1. 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. [PubMed:7284303]
  2. Jackson RC, Niethammer D, Hart LI: Reactivation of dihydrofolate reductase inhibted by methotrexate or aminopterin. Arch Biochem Biophys. 1977 Aug;182(2):646-56. [PubMed:561567]

Transporters

Kind
Protein
Organism
Human
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
  1. 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. [PubMed:22653877]

Drug created on May 14, 2013 13:45 / Updated on December 01, 2017 16:10