Identification

Name
Trimetrexate
Accession Number
DB01157  (APRD00268)
Type
Small Molecule
Groups
Approved, Investigational
Description

A nonclassical folic acid inhibitor through its inhibition of the enzyme dihydrofolate reductase. It is being tested for efficacy as an antineoplastic agent and as an antiparasitic agent against pneumocystis pneumonia in AIDS patients. Myelosuppression is its dose-limiting toxic effect.

Structure
Thumb
Synonyms
  • Trimetrexato
  • Trimetrexatum
Product Ingredients
IngredientUNIICASInChI Key
Trimetrexate glucuronateL137U4A79K82952-64-5ZCJXQWYMBJYJNB-LRDBBFHQSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Neutrexin Pws IV 25mg/vialPowder, for solution25 mgIntravenousMedimmune Oncology, Inc.1994-12-312007-02-21Canada
International/Other Brands
Neutrexin
Categories
UNII
UPN4ITI8T4
CAS number
52128-35-5
Weight
Average: 369.4176
Monoisotopic: 369.180089627
Chemical Formula
C19H23N5O3
InChI Key
NOYPYLRCIDNJJB-UHFFFAOYSA-N
InChI
InChI=1S/C19H23N5O3/c1-10-11(5-6-13-16(10)18(20)24-19(21)23-13)9-22-12-7-14(25-2)17(27-4)15(8-12)26-3/h5-8,22H,9H2,1-4H3,(H4,20,21,23,24)
IUPAC Name
5-methyl-6-{[(3,4,5-trimethoxyphenyl)amino]methyl}quinazoline-2,4-diamine
SMILES
COC1=CC(NCC2=C(C)C3=C(C=C2)N=C(N)N=C3N)=CC(OC)=C1OC

Pharmacology

Indication

For use, with concurrent leucovorin administration (leucovorin protection), as an alternative therapy for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with the acquired immunodeficiency syndrome (AIDS). Also used to treat several types of cancer including colon cancer.

Structured Indications
Not Available
Pharmacodynamics

Trimetrexate, a non-classical folate antagonist, is a synthetic inhibitor of the enzyme dihydrofolate reductase (DHFR). During DNA synthesis and cellular reproduction, folic acid is reduced to tetrahydrofolic acid by the enzyme folic acid reductase. By interfering with the reduction of folic acid, trimetrexate interferes with tissue cell reproduction. Generally, the most sensitive cells to the antimetabolite effect of trimetrexate are those cells which are most actively proliferating such as malignant cells, dermal epithelium, buccal and intestinal mucosa, bone marrow, fetal cells, and cells of the urinary bladder. Because the proliferation of cells in malignant tissues is greater than in most normal tissues, trimetrexate may impair the growth of the malignant tissues without causing irreversible damage to normal tissues. Due to very serious and potentially life-threatening side-effects of this drug, leucovorin must be co-administered for at least 72 hours after the last dose.

Mechanism of action

In vitro studies have shown that trimetrexate is a competitive inhibitor of dihydrofolate reductase (DHFR) from bacterial, protozoan, and mammalian sources. DHFR catalyzes the reduction of intracellular dihydrofolate to the active coenzyme tetrahydrofolate. Inhibition of DHFR results in the depletion of this coenzyme, leading directly to interference with thymidylate biosynthesis, as well as inhibition of folate-dependent formyltransferases, and indirectly to inhibition of p.r.n. biosynthesis. The end result is disruption of DNA, RNA, and protein synthesis, with consequent cell death.

TargetActionsOrganism
ADihydrofolate reductase
inhibitor
Human
Absorption
Not Available
Volume of distribution
  • 20 ± 8 L/m2
  • 36.9 ± 6 L/m2 [cancer patients]
Protein binding

95% (over the concentration range of 18.75 to 1000 ng/mL)

Metabolism

Hepatic. Preclinical data strongly suggest that the major metabolic pathway is oxidative O-demethylation, followed by conjugation to either glucuronide or the sulfate.

Route of elimination

Ten to 30% of the administered dose is excreted unchanged in the urine.

Half life

11 to 20 hours

Clearance
  • 38 +/- 15 mL/min/m2 [patients with acquired immunodeficiency syndrome (AIDS) who had Pneumocystis carinii pneumonia (4 patients) or toxoplasmosis (2 patients). Trimetrexate was administered intravenously as a bolus injection at a dose of 30 mg/m2/day along with leucovorin 20 mg/m2 every 6 hours for 21 days]
  • 53 +/- 41 mL/min/m2 [Cancer patients with advanced solid tumors using various dosage regimensreceiving a single-dose administration of 10 to 130 mg/m2]
  • 30 +/- 8 mL/min/m2 [Cancer patients with advanced solid tumors using various dosage regimensafter a five-day infusion]
Toxicity

The LD50 of intravenous trimetrexate in mice is 62 mg/kg (186 mg/m2). Myelosuppression is a dose-limiting toxic effect.

Affected organisms
  • Humans and other mammals
  • Pneumocystis carinii
  • Bacteria and protozoa
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Trimetrexate.Approved
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Trimetrexate.Experimental
AgmatineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Agmatine.Experimental, Investigational
AmiodaroneThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Amiodarone.Approved, Investigational
AmlodipineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Amlodipine.Approved
Amphotericin BThe therapeutic efficacy of Amphotericin B can be decreased when used in combination with Trimetrexate.Approved, Investigational
AmrinoneThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Amrinone.Approved
AncestimThe risk or severity of cytotoxicity can be increased when Ancestim is combined with Trimetrexate.Approved, Investigational, Withdrawn
AranidipineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Aranidipine.Approved, Investigational
AzelnidipineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Azelnidipine.Approved, Investigational
AzimilideThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Azimilide.Investigational
BarnidipineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Barnidipine.Approved
BencyclaneThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Bencyclane.Experimental
BenidipineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Benidipine.Approved, Investigational
BepridilThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Bepridil.Approved, Withdrawn
BevacizumabBevacizumab may increase the cardiotoxic activities of Trimetrexate.Approved, Investigational
BuspironeThe metabolism of Buspirone can be decreased when combined with Trimetrexate.Approved, Investigational
BusulfanThe serum concentration of Busulfan can be increased when it is combined with Trimetrexate.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Trimetrexate.Approved
CarboxyamidotriazoleThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Carboxyamidotriazole.Investigational
CaroverineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Caroverine.Experimental
CilnidipineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Cilnidipine.Approved, Investigational
CinnarizineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Cinnarizine.Approved, Investigational
CisaprideThe serum concentration of Cisapride can be increased when it is combined with Trimetrexate.Approved, Investigational, Withdrawn
ClevidipineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Clevidipine.Approved, Investigational
CyclandelateThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Cyclandelate.Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Trimetrexate.Approved, Investigational
CyclosporineThe metabolism of Cyclosporine can be decreased when combined with Trimetrexate.Approved, Investigational, Vet Approved
CymarinCymarin may decrease the cardiotoxic activities of Trimetrexate.Experimental
DarodipineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Darodipine.Experimental
DeslanosideDeslanoside may decrease the cardiotoxic activities of Trimetrexate.Approved
DidanosineDidanosine can cause a decrease in the absorption of Trimetrexate resulting in a reduced serum concentration and potentially a decrease in efficacy.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Trimetrexate.Approved, Investigational
DigoxinDigoxin may decrease the cardiotoxic activities of Trimetrexate.Approved
Digoxin Immune Fab (Ovine)Digoxin Immune Fab (Ovine) may decrease the cardiotoxic activities of Trimetrexate.Approved
DiltiazemThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Diltiazem.Approved, Investigational
DocetaxelThe metabolism of Docetaxel can be decreased when combined with Trimetrexate.Approved, Investigational
DofetilideThe serum concentration of Dofetilide can be increased when it is combined with Trimetrexate.Approved, Investigational
DotarizineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Dotarizine.Investigational
EfonidipineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Efonidipine.Approved, Investigational
EperisoneThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Eperisone.Approved, Investigational
EthosuximideThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Ethosuximide.Approved
EtravirineThe serum concentration of Etravirine can be increased when it is combined with Trimetrexate.Approved
FelodipineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Felodipine.Approved, Investigational
FendilineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Fendiline.Withdrawn
FlunarizineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Flunarizine.Approved
FluspirileneThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Fluspirilene.Approved, Investigational
FosphenytoinThe serum concentration of Trimetrexate can be decreased when it is combined with Fosphenytoin.Approved, Investigational
GabapentinThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Gabapentin.Approved, Investigational
GallopamilThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Gallopamil.Investigational
GitoformateGitoformate may decrease the cardiotoxic activities of Trimetrexate.Experimental
IsradipineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Isradipine.Approved, Investigational
LacidipineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Lacidipine.Approved, Investigational
LamotrigineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Lamotrigine.Approved, Investigational
Lanatoside CLanatoside C may decrease the cardiotoxic activities of Trimetrexate.Experimental
LercanidipineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Lercanidipine.Approved, Investigational
LevetiracetamThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Levetiracetam.Approved, Investigational
LidoflazineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Lidoflazine.Experimental
LipegfilgrastimTrimetrexate may increase the myelosuppressive activities of Lipegfilgrastim.Approved, Investigational
LoperamideThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Loperamide.Approved
LosartanThe metabolism of Losartan can be decreased when combined with Trimetrexate.Approved
Magnesium sulfateThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Magnesium sulfate.Approved, Investigational, Vet Approved
ManidipineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Manidipine.Approved, Investigational
MethsuximideThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Methsuximide.Approved
MetildigoxinMetildigoxin may decrease the cardiotoxic activities of Trimetrexate.Experimental
MibefradilThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Mibefradil.Investigational, Withdrawn
NaftopidilThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Naftopidil.Investigational
NicardipineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Nicardipine.Approved, Investigational
NifedipineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Nifedipine.Approved
NiguldipineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Niguldipine.Experimental
NiludipineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Niludipine.Experimental
NilvadipineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Nilvadipine.Approved, Investigational
NimesulideThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Nimesulide.Approved, Investigational, Withdrawn
NimodipineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Nimodipine.Approved, Investigational
NisoldipineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Nisoldipine.Approved
NitrendipineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Nitrendipine.Approved, Investigational
NylidrinThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Nylidrin.Approved
OleandrinOleandrin may decrease the cardiotoxic activities of Trimetrexate.Experimental, Investigational
OtiloniumThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Otilonium.Experimental, Investigational
OuabainOuabain may decrease the cardiotoxic activities of Trimetrexate.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Trimetrexate.Approved, Vet Approved
PeruvosidePeruvoside may decrease the cardiotoxic activities of Trimetrexate.Experimental
PhenytoinThe serum concentration of Phenytoin can be increased when it is combined with Trimetrexate.Approved, Vet Approved
PinaveriumThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Pinaverium.Approved
PrenylamineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Prenylamine.Withdrawn
ProgesteroneThe absorption of Progesterone can be decreased when combined with Trimetrexate.Approved, Vet Approved
ProscillaridinProscillaridin may decrease the cardiotoxic activities of Trimetrexate.Experimental
QuinidineThe serum concentration of Quinidine can be increased when it is combined with Trimetrexate.Approved, Investigational
RanolazineThe serum concentration of Ranolazine can be increased when it is combined with Trimetrexate.Approved, Investigational
RifabutinThe serum concentration of Rifabutin can be increased when it is combined with Trimetrexate.Approved, Investigational
RifampicinThe serum concentration of Rifampicin can be increased when it is combined with Trimetrexate.Approved
RifapentineThe serum concentration of Rifapentine can be increased when it is combined with Trimetrexate.Approved, Investigational
RifaximinThe serum concentration of Rifaximin can be increased when it is combined with Trimetrexate.Approved, Investigational
SeletracetamThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Seletracetam.Investigational
SolifenacinThe metabolism of Solifenacin can be decreased when combined with Trimetrexate.Approved
SucralfateSucralfate can cause a decrease in the absorption of Trimetrexate resulting in a reduced serum concentration and potentially a decrease in efficacy.Approved
SunitinibThe metabolism of Sunitinib can be decreased when combined with Trimetrexate.Approved, Investigational
TacrolimusThe metabolism of Tacrolimus can be decreased when combined with Trimetrexate.Approved, Investigational
TerodilineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Terodiline.Experimental
TetrahydropalmatineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Tetrahydropalmatine.Investigational
Tolfenamic AcidThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Tolfenamic Acid.Approved, Investigational
TranilastThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Tranilast.Approved, Investigational
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Trimetrexate.Approved, Investigational
TrimebutineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Trimebutine.Approved
TrimethadioneThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Trimethadione.Approved
VerapamilThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Verapamil.Approved
VinpocetineThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Vinpocetine.Investigational
WIN 55212-2The therapeutic efficacy of Trimetrexate can be increased when used in combination with WIN 55212-2.Experimental
ZiconotideThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Ziconotide.Approved
ZolpidemThe serum concentration of Zolpidem can be increased when it is combined with Trimetrexate.Approved
ZonisamideThe therapeutic efficacy of Trimetrexate can be increased when used in combination with Zonisamide.Approved, Investigational
Food Interactions
Not Available

References

Synthesis Reference

Martin Stogniew, Javad M. Zadei, "Compositions comprising trimetrexate and methods of their synthesis and use." U.S. Patent US6258821, issued January, 1974.

US6258821
General References
Not Available
External Links
Human Metabolome Database
HMDB0015288
KEGG Drug
D06238
KEGG Compound
C11154
PubChem Compound
5583
PubChem Substance
46505247
ChemSpider
5381
BindingDB
18268
ChEMBL
CHEMBL119
Therapeutic Targets Database
DAP000635
PharmGKB
PA451790
HET
TMQ
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Trimetrexate
ATC Codes
P01AX07 — Trimetrexate
FDA label
Download (53.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Pneumonia, Pneumocystis Carinii2
1CompletedTreatmentSarcomas1
2Active Not RecruitingTreatmentDesmoid Tumors1
2Active Not RecruitingTreatmentEstrogen Receptor-Positive Breast Cancer / HER2-Negative Breast Cancer / Progesterone Receptor-positive Breast Cancer / Recurrent Breast Cancer / Stage IIIA Breast Cancer / Stage IIIB Breast Cancer / Stage IIIC Breast Cancer / Stage IV Breast Cancer1
2CompletedTreatmentColorectal Cancers1
2CompletedTreatmentDuctal Breast Carcinoma In Situ / Estrogen Receptor-Positive Breast Cancer1
2CompletedTreatmentEstrogen Receptor-negative Breast Cancer / Estrogen Receptor-Positive Breast Cancer / Her2-Positive Breast Cancer / Progesterone Receptor-negative Breast Cancer / Progesterone Receptor-positive Breast Cancer / Stage IA Breast Cancer / Stage IB Breast Cancer / Stage II Breast Cancer / Stage IIIA Breast Cancer1
2CompletedTreatmentEstrogen Receptor-negative Breast Cancer / Estrogen Receptor-Positive Breast Cancer / Inflammatory carcinoma of the breast / Male Breast Cancer / Progesterone Receptor-negative Breast Cancer / Progesterone Receptor-positive Breast Cancer / Stage IIIB Breast Cancer / Stage IV Breast Cancer1
2CompletedTreatmentLeukemias / Malignant Lymphomas / Sarcomas1
2CompletedTreatmentMale Breast Cancer / Stage II Breast Cancer / Stage IIIA Breast Cancer / Stage IIIB Breast Cancer1
2CompletedTreatmentMalignant Neoplasm of Pancreas1
2CompletedTreatmentSarcomas1
3CompletedTreatmentFallopian Tube Cancer / Primary Peritoneal Cavity Cancer / Recurrent Ovarian Epithelial Cancer / Stage III Ovarian Epithelial Cancer / Stage IV Ovarian Epithelial Cancer1
3CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Pneumonia, Pneumocystis Carinii5
3TerminatedTreatmentCardiac Toxicity / Inflammatory carcinoma of the breast / Stage IIIA Breast Cancer / Stage IIIB Breast Cancer / Stage IV Breast Cancer1
3TerminatedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Pneumonia, Pneumocystis Carinii1
Not AvailableCompletedTreatmentDuctal Breast Carcinoma In Situ / Lobular Breast Carcinoma In Situ / Stage II Breast Cancer / Stage IIA Breast Cancer / Stage IIB Breast Cancer / Stage IIIA Breast Cancer / Stage IIIB Breast Cancer1
Not AvailableCompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Pneumonia, Pneumocystis Carinii4

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Ben Venue Laboratories Inc.
  • Medimmune Inc.
Dosage forms
FormRouteStrength
Powder, for solutionIntravenous25 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6017922No1998-05-182018-05-18Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)215-217 °CPhysProp
water solubility31.4 mg/LNot Available
logP2.55HANSCH,C ET AL. (1995)
pKa8.0Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0309 mg/mLALOGPS
logP2.36ALOGPS
logP2.28ChemAxon
logS-4.1ALOGPS
pKa (Strongest Acidic)17.04ChemAxon
pKa (Strongest Basic)7.54ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area117.54 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity107.7 m3·mol-1ChemAxon
Polarizability40.24 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9382
Caco-2 permeable+0.6393
P-glycoprotein substrateSubstrate0.5758
P-glycoprotein inhibitor INon-inhibitor0.5948
P-glycoprotein inhibitor IINon-inhibitor0.6545
Renal organic cation transporterNon-inhibitor0.7837
CYP450 2C9 substrateNon-substrate0.8668
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateNon-substrate0.5206
CYP450 1A2 substrateNon-inhibitor0.5
CYP450 2C9 inhibitorNon-inhibitor0.7037
CYP450 2D6 inhibitorNon-inhibitor0.7397
CYP450 2C19 inhibitorNon-inhibitor0.6512
CYP450 3A4 inhibitorNon-inhibitor0.8614
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6235
Ames testNon AMES toxic0.6339
CarcinogenicityNon-carcinogens0.9136
BiodegradationNot ready biodegradable0.9968
Rat acute toxicity2.3340 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9027
hERG inhibition (predictor II)Non-inhibitor0.6892
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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 quinazolinamines. These are heterocyclic aromatic compounds containing a quianazoline moiety substituted by one or more amine groups.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazanaphthalenes
Sub Class
Benzodiazines
Direct Parent
Quinazolinamines
Alternative Parents
Methoxyanilines / Aminophenyl ethers / Phenylalkylamines / Phenoxy compounds / Methoxybenzenes / Anisoles / Secondary alkylarylamines / Aminopyrimidines and derivatives / Alkyl aryl ethers / Imidolactams
show 5 more
Substituents
Quinazolinamine / Methoxyaniline / Aminophenyl ether / Aniline or substituted anilines / Phenylalkylamine / Phenoxy compound / Methoxybenzene / Phenol ether / Anisole / Secondary aliphatic/aromatic amine
show 20 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Details
1. Dihydrofolate reductase
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 pre...
Gene Name
DHFR
Uniprot ID
P00374
Uniprot Name
Dihydrofolate reductase
Molecular Weight
21452.61 Da
References
  1. Bertino JR, Zhao SC, Mineishi S, Ercikan-Abali EA, Banerjee D: Use of variants of dihydrofolate reductase in gene transfer to produce resistance to methotrexate and trimetrexate. Prog Exp Tumor Res. 1999;36:82-94. [PubMed:10386066]
  2. Graffner-Nordberg M, Kolmodin K, Aqvist J, Queener SF, Hallberg A: Design, synthesis, computational prediction, and biological evaluation of ester soft drugs as inhibitors of dihydrofolate reductase from Pneumocystis carinii. J Med Chem. 2001 Jul 19;44(15):2391-402. [PubMed:11448221]
  3. Warlick CA, Diers MD, Wagner JE, McIvor RS: In vivo selection of antifolate-resistant transgenic hematopoietic stem cells in a murine bone marrow transplant model. J Pharmacol Exp Ther. 2002 Jan;300(1):50-6. [PubMed:11752096]
  4. Zhu WY, Bunni M, Priest DG, DiCapua JL, Dressler JM, Chen Z, Melera PW: Severe folate restriction results in depletion of and alteration in the composition of the intracellular folate pool, moderate sensitization to methotrexate and trimetrexate, upregulation of endogenous DHFR activity, and overexpression of metallothionein II and folate receptor alpha that, upon folate repletion, confer drug resistance to CHL cells. J Exp Ther Oncol. 2002 Sep-Oct;2(5):264-77. [PubMed:12416030]
  5. Sweeney CL, Frandsen JL, Verfaillie CM, McIvor RS: Trimetrexate inhibits progression of the murine 32Dp210 model of chronic myeloid leukemia in animals expressing drug-resistant dihydrofolate reductase. Cancer Res. 2003 Mar 15;63(6):1304-10. [PubMed:12649191]
  6. Polshakov VI, Birdsall B, Frenkiel TA, Gargaro AR, Feeney J: Structure and dynamics in solution of the complex of Lactobacillus casei dihydrofolate reductase with the new lipophilic antifolate drug trimetrexate. Protein Sci. 1999 Mar;8(3):467-81. [PubMed:10091649]
  7. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Drug created on June 13, 2005 07:24 / Updated on March 02, 2018 05:35