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Identification
NamePralatrexate
Accession NumberDB06813
TypeSmall Molecule
GroupsApproved
Description

Pralatrexate is an antimetabolite for the treatment of relapsed or refractory peripheral T-cell lymphoma. It is more efficiently retained in cancer cells than methotrexate. FDA approved on September 24, 2009.

Structure
Thumb
Synonyms
(2S)-2-((4-((1RS)-1-((2,4-diaminopteridin-6-yl)methyl)but-3-ynyl)benzoyl)amino)pentanedioic acid
(2S)-2-({4-[1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl]benzoyl}amino)pentanedioic acid
10-Propargyl-10-deazaaminopterin
Folotyn
HSDB 7786
N-(4-(1-((2,4-Diamino-6-pteridinyl)methyl)-3-butynyl)benzoyl)-L-glutamic acid
PDX
Pralatrexato
Pralatrexatum
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Folotyninjection20 mg/mLintravenousAllos Therapeutics2009-09-24Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIA8Q8I19Q20
CAS number146464-95-1
WeightAverage: 477.4726
Monoisotopic: 477.176066881
Chemical FormulaC23H23N7O5
InChI KeyInChIKey=OGSBUKJUDHAQEA-WMCAAGNKSA-N
InChI
InChI=1S/C23H23N7O5/c1-2-3-14(10-15-11-26-20-18(27-15)19(24)29-23(25)30-20)12-4-6-13(7-5-12)21(33)28-16(22(34)35)8-9-17(31)32/h1,4-7,11,14,16H,3,8-10H2,(H,28,33)(H,31,32)(H,34,35)(H4,24,25,26,29,30)/t14?,16-/m0/s1
IUPAC Name
(2S)-2-({4-[1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl]phenyl}formamido)pentanedioic acid
SMILES
NC1=NC2=NC=C(CC(CC#C)C3=CC=C(C=C3)C(=O)N[C@@H](CCC(O)=O)C(O)=O)N=C2C(N)=N1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as hippuric acids. These are compounds containing hippuric acid, which consists of a of a benzoyl group linked to the N-terminal of a glycine.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassBenzamides
Direct ParentHippuric acids
Alternative Parents
Substituents
  • N-acyl-alpha amino acid or derivatives
  • N-acyl-alpha-amino acid
  • Hippuric acid
  • Pteridine
  • Monoterpenoid
  • Bicyclic monoterpenoid
  • Aromatic monoterpenoid
  • P-cymene
  • Alpha-amino acid or derivatives
  • N-substituted-alpha-amino acid
  • Benzoic acid or derivatives
  • Benzoyl
  • Aminopyrimidine
  • Amino fatty acid
  • Fatty acyl
  • Imidolactam
  • Pyrimidine
  • Pyrazine
  • Primary aromatic amine
  • Dicarboxylic acid or derivatives
  • Heteroaromatic compound
  • Secondary carboxylic acid amide
  • Carboxamide group
  • Azacycle
  • Organoheterocyclic compound
  • 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
IndicationTreatment of relapsed or refractory peripheral T-cell lymphoma.
PharmacodynamicsPralatrexate is a 10-deazaaminopterin analogue of methotrexate. Compared to methotrexate, pralatrexate binds to RTC-1 with 10-times the affinity and is a more potent substrate for FPGS. As a result, pralatrexate is better internalized and retained in cancer cells and is more cytotoxic. Km, pralatrexate = 0.3 μmol/L; Km, methotrexate = 4.8 μmol/L; Vmax/Km (rate of intracellular transport), pralatrexate = 12.6 Vmax/Km (rate of intracellular transport), methotrexate = 0.9
Mechanism of actionThe selectivity of pralatrexate for cancer cells is based upon the observation that cancer cells generally have an overexpression of reduced folate carrier protein-1 (RTC-1) compared to normal somatic cells. This carrier protein allows the entrance of pralatrexate into the cell. Upon entering the cell, folypolyglutamate synthase FPGS catalyzes the polyglutamination of pralatrexate so that it is retained inside the cell. Once inside, pralatrexate competitively inhibits dihydrofolate reductase (DHFR) and thymidylate synthase. Subsequent depletion of thymidine monophosphate (TMP) occurs so that the cancer cell is unable to synthesize DNA and RNA. As a result, the cancer cell cannot proliferate and is forced to undergo apoptosis. Pralatrexate is more effective against cells that are actively dividing.
Related Articles
AbsorptionPralatrexate demonstrates linear pharmacokinetics with a multiphasic decline with both diasteromers over dose range of 30-325 mg/m^2. Bioavailability, nonformulated preparation = 13 - 20%
Volume of distribution

Vss, R-pralatrexate = 37 L
Vss, S-pralatrexate = 105 L

Protein binding67 - 86% bound to plasma protein, albumin is the major binder. Does not significantly displace substrates from proteins.
Metabolism

No involvement of CYP450 enzyme system or glucuronidases.

Route of elimination35% of drug is excreted unchanged in the urine (no difference between R- and S- pralatrexate). May be some net renal tubular excretion.
Half life12-18 hours
Clearance

R- pralatrexate = 191 mL/min
S- pralatrexate = 417 mL/min
Mean clearance of both enantiomers is 220 mL/min.

ToxicityMucositis is the dose-limiting toxicity. Folic acid and vitamin B12 supplements do not prevent mucositis from happening.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.6139
Blood Brain Barrier+0.5561
Caco-2 permeable-0.7518
P-glycoprotein substrateSubstrate0.5845
P-glycoprotein inhibitor INon-inhibitor0.9224
P-glycoprotein inhibitor IINon-inhibitor0.9921
Renal organic cation transporterNon-inhibitor0.938
CYP450 2C9 substrateNon-substrate0.8589
CYP450 2D6 substrateNon-substrate0.8269
CYP450 3A4 substrateNon-substrate0.6396
CYP450 1A2 substrateNon-inhibitor0.8654
CYP450 2C9 inhibitorNon-inhibitor0.8965
CYP450 2D6 inhibitorNon-inhibitor0.9073
CYP450 2C19 inhibitorNon-inhibitor0.9178
CYP450 3A4 inhibitorNon-inhibitor0.6523
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.934
Ames testNon AMES toxic0.8727
CarcinogenicityNon-carcinogens0.9543
BiodegradationNot ready biodegradable0.9493
Rat acute toxicity2.6263 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9803
hERG inhibition (predictor II)Non-inhibitor0.8735
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Injectionintravenous20 mg/mL
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6028071 No2002-07-162022-07-16Us
US7622470 No2005-05-312025-05-31Us
US8299078 No2005-05-312025-05-31Us
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.0178 mg/mLALOGPS
logP0.1ALOGPS
logP0.33ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)3.44ChemAxon
pKa (Strongest Basic)2.86ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count11ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area207.3 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity126.82 m3·mol-1ChemAxon
Polarizability47.31 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
References
Synthesis ReferenceNot Available
General References
  1. Shimanovsky A, Dasanu CA: Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma. Expert Opin Pharmacother. 2013 Mar;14(4):515-23. doi: 10.1517/14656566.2013.770474. Epub 2013 Feb 14. [PubMed:23409799 ]
  2. Gonen N, Assaraf YG: Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist Updat. 2012 Aug;15(4):183-210. doi: 10.1016/j.drup.2012.07.002. Epub 2012 Aug 23. [PubMed:22921318 ]
  3. Rodd AL, Ververis K, Karagiannis TC: Safety and efficacy of pralatrexate in the management of relapsed or refractory peripheral T-cell lymphoma. Clin Med Insights Oncol. 2012;6:305-14. doi: 10.4137/CMO.S8536. Epub 2012 Aug 21. [PubMed:23032692 ]
External Links
ATC CodesL01BA05
AHFS Codes
  • 10:00
PDB EntriesNot Available
FDA labelDownload (266 KB)
MSDSDownload (479 KB)
Interactions
Drug Interactions
Drug
Acetylsalicylic acidThe serum concentration of Pralatrexate can be increased when it is combined with Acetylsalicylic acid.
Aminosalicylic AcidThe serum concentration of Pralatrexate can be increased when it is combined with Aminosalicylic Acid.
Bismuth SubsalicylateThe serum concentration of Pralatrexate can be increased when it is combined with Bismuth Subsalicylate.
CelecoxibThe serum concentration of Pralatrexate can be increased when it is combined with Celecoxib.
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Pralatrexate.
DiclofenacThe serum concentration of Pralatrexate can be increased when it is combined with Diclofenac.
DiflunisalThe serum concentration of Pralatrexate can be increased when it is combined with Diflunisal.
EtodolacThe serum concentration of Pralatrexate can be increased when it is combined with Etodolac.
FenoprofenThe serum concentration of Pralatrexate can be increased when it is combined with Fenoprofen.
FloctafenineThe serum concentration of Pralatrexate can be increased when it is combined with Floctafenine.
FlurbiprofenThe serum concentration of Pralatrexate can be increased when it is combined with Flurbiprofen.
IbuprofenThe serum concentration of Pralatrexate can be increased when it is combined with Ibuprofen.
IndomethacinThe serum concentration of Pralatrexate can be increased when it is combined with Indomethacin.
InfliximabThe serum concentration of Pralatrexate can be increased when it is combined with Infliximab.
KetoprofenThe serum concentration of Pralatrexate can be increased when it is combined with Ketoprofen.
KetorolacThe serum concentration of Pralatrexate can be increased when it is combined with Ketorolac.
LeflunomideThe risk or severity of adverse effects can be increased when Pralatrexate is combined with Leflunomide.
Magnesium salicylateThe serum concentration of Pralatrexate can be increased when it is combined with Magnesium salicylate.
Mefenamic acidThe serum concentration of Pralatrexate can be increased when it is combined with Mefenamic acid.
MeloxicamThe serum concentration of Pralatrexate can be increased when it is combined with Meloxicam.
NabumetoneThe serum concentration of Pralatrexate can be increased when it is combined with Nabumetone.
NaproxenThe serum concentration of Pralatrexate can be increased when it is combined with Naproxen.
NatalizumabThe risk or severity of adverse effects can be increased when Pralatrexate is combined with Natalizumab.
OxaprozinThe serum concentration of Pralatrexate can be increased when it is combined with Oxaprozin.
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Pralatrexate.
PiroxicamThe serum concentration of Pralatrexate can be increased when it is combined with Piroxicam.
ProbenecidThe serum concentration of Pralatrexate can be increased when it is combined with Probenecid.
RoflumilastRoflumilast may increase the immunosuppressive activities of Pralatrexate.
SalsalateThe serum concentration of Pralatrexate can be increased when it is combined with Salsalate.
SapropterinThe serum concentration of Tetrahydrobiopterin can be decreased when it is combined with Pralatrexate.
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Pralatrexate.
SulfamethoxazoleThe serum concentration of Pralatrexate can be increased when it is combined with Sulfamethoxazole.
SulindacThe serum concentration of Pralatrexate can be increased when it is combined with Sulindac.
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Pralatrexate.
Tiaprofenic acidThe serum concentration of Pralatrexate can be increased when it is combined with Tiaprofenic acid.
TofacitinibPralatrexate may increase the immunosuppressive activities of Tofacitinib.
TolmetinThe serum concentration of Pralatrexate can be increased when it is combined with Tolmetin.
TrastuzumabTrastuzumab may increase the neutropenic activities of Pralatrexate.
TrimethoprimThe serum concentration of Pralatrexate can be increased when it is combined with Trimethoprim.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
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 precursor synthesis. Binds its own mRNA and that of DHFRL1.
Gene Name:
DHFR
Uniprot ID:
P00374
Molecular Weight:
21452.61 Da
References
  1. Shimanovsky A, Dasanu CA: Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma. Expert Opin Pharmacother. 2013 Mar;14(4):515-23. doi: 10.1517/14656566.2013.770474. Epub 2013 Feb 14. [PubMed:23409799 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Thymidylate synthase activity
Specific Function:
Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.
Gene Name:
TYMS
Uniprot ID:
P04818
Molecular Weight:
35715.65 Da
References
  1. Shimanovsky A, Dasanu CA: Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma. Expert Opin Pharmacother. 2013 Mar;14(4):515-23. doi: 10.1517/14656566.2013.770474. Epub 2013 Feb 14. [PubMed:23409799 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Tetrahydrofolylpolyglutamate synthase activity
Specific Function:
Catalyzes conversion of folates to polyglutamate derivatives allowing concentration of folate compounds in the cell and the intracellular retention of these cofactors, which are important substrates for most of the folate-dependent enzymes that are involved in one-carbon transfer reactions involved in purine, pyrimidine and amino acid synthesis. Unsubstituted reduced folates are the preferred s...
Gene Name:
FPGS
Uniprot ID:
Q05932
Molecular Weight:
64608.53 Da
References
  1. Shimanovsky A, Dasanu CA: Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma. Expert Opin Pharmacother. 2013 Mar;14(4):515-23. doi: 10.1517/14656566.2013.770474. Epub 2013 Feb 14. [PubMed:23409799 ]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Reduced folate carrier activity
Specific Function:
Transporter for the intake of folate. Uptake of folate in human placental choriocarcinoma cells occurs by a novel mechanism called potocytosis which functionally couples three components, namely the folate receptor, the folate transporter, and a V-type H(+)-pump.
Gene Name:
SLC19A1
Uniprot ID:
P41440
Molecular Weight:
64867.62 Da
References
  1. Gonen N, Assaraf YG: Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist Updat. 2012 Aug;15(4):183-210. doi: 10.1016/j.drup.2012.07.002. Epub 2012 Aug 23. [PubMed:22921318 ]
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Drug created on September 14, 2010 10:21 / Updated on August 24, 2016 01:52