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Identification
NameAminopterin
Accession NumberDB08878
TypeSmall Molecule
GroupsInvestigational, Withdrawn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
SynonymLanguageCode
4-amino-4-deoxypteroylglutamateNot AvailableNot Available
4-amino-PGANot AvailableNot Available
4-aminofolic acidNot AvailableNot Available
4-aminopteroylglutamic acidNot AvailableNot Available
4'-Amino-folsaeureNot AvailableNot Available
A-ninopterinNot AvailableNot Available
A-NinopterinNot AvailableNot Available
AminopteridineNot AvailableNot Available
AminopterineNot AvailableNot Available
APGANot AvailableNot Available
Minopterin Not AvailableNot Available
N-(4-{[(2,4-Diamino-6-pteridinyl)methyl]amino}benzoyl)glutamic acidNot AvailableNot Available
PteraminaNot AvailableNot Available
Prescription ProductsNot Available
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
CAS number54-62-6
WeightAverage: 440.4127
Monoisotopic: 440.15566579
Chemical FormulaC19H20N8O5
InChI KeyTVZGACDUOSZQKY-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
Taxonomy
DescriptionThis 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.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassPteridines and derivatives
Sub ClassPterins and derivatives
Direct ParentFolic acids
Alternative Parents
Substituents
  • Folic acid
  • N-acyl-alpha amino acid or derivatives
  • N-acyl-alpha-amino acid
  • Hippuric acid
  • Hippuric acid or derivatives
  • Aminobenzoic acid or derivatives
  • Alpha-amino acid or derivatives
  • N-substituted-alpha-amino acid
  • Benzoic acid or derivatives
  • Benzamide
  • Aminobenzamide
  • Phenylalkylamine
  • Substituted aniline
  • Benzoyl
  • Aralkylamine
  • Secondary aliphatic/aromatic amine
  • Aniline
  • Aminopyrimidine
  • Amino fatty acid
  • Fatty acyl
  • Imidolactam
  • Benzenoid
  • Pyrimidine
  • Pyrazine
  • Primary aromatic amine
  • Dicarboxylic acid or derivatives
  • Monocyclic benzene moiety
  • Heteroaromatic compound
  • Secondary carboxylic acid amide
  • Carboxamide group
  • Azacycle
  • Secondary amine
  • Carboxylic acid
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Primary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationPrior 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.
PharmacodynamicsNot Available
Mechanism of actionAminopterin 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.
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityNot Available
Affected organismsNot Available
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 substrateNon-inhibitor0.9199
CYP450 2D6 substrateNon-inhibitor0.933
CYP450 2C19 substrateNon-inhibitor0.9382
CYP450 3A4 substrateNon-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
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point225 °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 FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Download (20.5 KB)
SpectraNot Available
References
Synthesis Reference

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

General Reference
  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
  2. Wheeler M, O’Meara P, Stanford M: Fetal methotrexate and misoprostol exposure: the past revisited. Teratology. 2002 Aug;66(2):73-6. Pubmed
  3. NICHOL CA, WELCH AD: On the mechanism of action of aminopterin. Proc Soc Exp Biol Med. 1950 Jun;74(2):403-11. Pubmed
  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
  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
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (42.3 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Enzymes

1. Dihydrofolate reductase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Dihydrofolate reductase P00374 Details

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
  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

Transporters

1. Proton-coupled folate transporter

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Proton-coupled folate transporter Q96NT5 Details

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

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Drug created on May 14, 2013 13:45 / Updated on January 01, 2014 21:10