IDPharmacologyInteractionsReferencesTrialsEconomicsPropertiesSpectraTaxonomy
Targets (2)
Targets (2)Biointeractions (2)
Identification
NameRaltitrexed
Accession NumberDB00293  (APRD00430, EXPT01092)
TypeSmall Molecule
GroupsApproved, Investigational
Description

Raltitrexed (brand name Tomudex®) is a chemotherapy drug manufactured AstraZeneca Company, is an antimetabolite used in chemotherapy. It is an inhibitor of thymidylate synthase.

Structure
Thumb
MOLSDF3D-SDFPDBSMILESInChI View 3D Structure
Synonyms
Raltitrexed
Tomudex
External IDs ZD 1694 / ZD-1694 / ZD1694
Product Ingredients Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
TomudexPowder, for solution2 mgIntravenousHospira, Inc.1996-11-18Not applicableCanada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Categories
UNIIFCB9EGG971
CAS number112887-68-0
WeightAverage: 458.488
Monoisotopic: 458.126005146
Chemical FormulaC21H22N4O6S
InChI KeyIVTVGDXNLFLDRM-HNNXBMFYSA-N
InChI
InChI=1S/C21H22N4O6S/c1-11-22-14-4-3-12(9-13(14)19(28)23-11)10-25(2)17-7-6-16(32-17)20(29)24-15(21(30)31)5-8-18(26)27/h3-4,6-7,9,15H,5,8,10H2,1-2H3,(H,24,29)(H,26,27)(H,30,31)(H,22,23,28)/t15-/m0/s1
IUPAC Name
(2S)-2-[(5-{methyl[(2-methyl-4-oxo-1,4-dihydroquinazolin-6-yl)methyl]amino}thiophen-2-yl)formamido]pentanedioic acid
SMILES
CN(CC1=CC2=C(NC(C)=NC2=O)C=C1)C1=CC=C(S1)C(=O)N[C@@H](CCC(O)=O)C(O)=O
Pharmacology
Indication

For the treatment of malignant neoplasm of colon and rectum

Structured Indications
Pharmacodynamics

Raltitrexed belongs to a group of medicines known as antimetabolites. It is used to treat cancer of the colon and rectum. It may also be used to treat other kinds of cancer, as determined by your doctor. Raltitrexed blocks an enzyme needed by the cell to live. This interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by raltitrexed, other effects will also occur. Some of these may be serious and must be reported to your doctor. Other effects, like hair loss, may not be serious but may cause concern.

Mechanism of action

Raltitrexed is an antineoplastic Agents and folic acid antagonists. Raltitrexed inhibits thymidylate synthase (TS) leading to DNA fragmentation and cell death. It is transported into cells via a reduced folate carrier. Inside the cell Raltitrexed is extensively polyglutamated, which enhances thymidylate synthase inhibitory power and duration. Inhibition of this enzyme results in decreased synthesis of thymidine triphosphate which is required for DNA synthesis.

TargetKindPharmacological actionActionsOrganismUniProt ID
Thymidylate synthaseProteinyes
inhibitor
HumanP04818 details
Folylpolyglutamate synthase, mitochondrialProteinunknown
antagonist
HumanQ05932 details
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein binding

>93%

Metabolism

Raltitrexed is transported into cells via a reduced folate carrier. Inside the cell it is extensively polyglutamated by the enzyme folyl polyglutamate synthetase to polyglutamate forms.

Route of eliminationNot Available
Half life

198 hours

ClearanceNot Available
Toxicity

Side effects include pale skin, troubled breathing, unusual bleeding or bruising, unusual tiredness or weakness, black, tarry stools, chest pain, chills, cough, fever, painful or difficult urination, shortness of breath, sore throat, sores, ulcers, or white spots on lips or in mouth, swollen glands, increase in bowel movements, loose stools, soft stools.

Affected organisms
  • Humans and other mammals
PathwaysNot Available
Pharmacogenomic Effects/ADRs Not Available
Interactions
Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Raltitrexed.Approved
BCG vaccineThe therapeutic efficacy of Bcg can be decreased when used in combination with Raltitrexed.Investigational
BevacizumabBevacizumab may increase the cardiotoxic activities of Raltitrexed.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Raltitrexed.Approved
ClozapineThe risk or severity of adverse effects can be increased when Raltitrexed is combined with Clozapine.Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Raltitrexed.Approved, Investigational
DeslanosideDeslanoside may decrease the cardiotoxic activities of Raltitrexed.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Raltitrexed.Approved
DigoxinDigoxin may decrease the cardiotoxic activities of Raltitrexed.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Raltitrexed.Approved, Investigational
Folic AcidThe therapeutic efficacy of Raltitrexed can be decreased when used in combination with Folic Acid.Approved, Nutraceutical, Vet Approved
LeucovorinThe therapeutic efficacy of Raltitrexed can be decreased when used in combination with Leucovorin.Approved
LevoleucovorinThe therapeutic efficacy of Raltitrexed can be decreased when used in combination with Levoleucovorin.Approved
Levomefolic acidThe therapeutic efficacy of Raltitrexed can be decreased when used in combination with Levomefolic acid.Approved
MetamizoleThe risk or severity of adverse effects can be increased when Metamizole is combined with Raltitrexed.Withdrawn
OleandrinAnvirzel may decrease the cardiotoxic activities of Raltitrexed.Experimental
OuabainOuabain may decrease the cardiotoxic activities of Raltitrexed.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Raltitrexed.Approved, Vet Approved
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Raltitrexed.Approved, Investigational
Food InteractionsNot Available
References
Synthesis ReferenceUS4992550
General ReferencesNot Available
External Links
ATC CodesL01BA03 — Raltitrexed
AHFS Codes
  • 92:00.00
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (57 KB)
Clinical Trials
Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentColorectal Cancers1
1CompletedTreatmentNeoplasms1
1CompletedTreatmentRecurrent Childhood Acute Lymphoblastic Leukemia / Recurrent Childhood Acute Myeloid Leukemia1
1CompletedTreatmentUnspecified Adult Solid Tumor, Protocol Specific2
2Active Not RecruitingTreatmentRectal Carcinoma1
2CompletedTreatmentAdenocarcinoma of Colon / Adenocarcinoma of Rectum / Metastatic Disease1
2CompletedTreatmentInoperable or Recurrent Rectal Cancer1
2CompletedTreatmentMesothelioma, Malignant1
2CompletedTreatmentRectal Neoplasms1
2Not Yet RecruitingTreatmentMetastatic Colon Cancer1
2RecruitingTreatmentColorectal Cancers1
2RecruitingTreatmentColorectal Cancers / Hepatic Metastases1
2RecruitingTreatmentGastroesophageal Junction Adenocarcinoma / Malignant Neoplasm of Stomach1
2RecruitingTreatmentNasopharyngeal Carcinoma1
2RecruitingTreatmentRectal Neoplasms Malignant1
2Unknown StatusTreatmentCarcinoma, Colorectal1
2Unknown StatusTreatmentInoperable Esophageal Cancer Stage I-III1
2, 3CompletedTreatmentColorectal Cancers1
3CompletedTreatmentMesothelioma, Malignant1
3RecruitingTreatmentHead and Neck Squamous Cell Cancer1
3Unknown StatusTreatmentColorectal Cancers1
4Not Yet RecruitingTreatmentHead and Neck Squamous Cell Carcinoma (HNSCC)1
4RecruitingTreatmentColon Cancer Liver Metastasis1
4RecruitingTreatmentMetastatic Colorectal Cancers1
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Powder, for solutionIntravenous2 mg
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point (°C)180-184 °CNot Available
water solubilitysolubleNot Available
logP-1.2Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0181 mg/mLALOGPS
logP1.65ALOGPS
logP1.97ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)3.72ChemAxon
pKa (Strongest Basic)-0.46ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count9ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area148.4 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity117.39 m3·mol-1ChemAxon
Polarizability45.55 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.6717
Blood Brain Barrier-0.9044
Caco-2 permeable-0.7873
P-glycoprotein substrateSubstrate0.7093
P-glycoprotein inhibitor INon-inhibitor0.9214
P-glycoprotein inhibitor IINon-inhibitor0.9588
Renal organic cation transporterNon-inhibitor0.8799
CYP450 2C9 substrateNon-substrate0.7133
CYP450 2D6 substrateNon-substrate0.8077
CYP450 3A4 substrateSubstrate0.6032
CYP450 1A2 substrateNon-inhibitor0.7801
CYP450 2C9 inhibitorNon-inhibitor0.5435
CYP450 2D6 inhibitorNon-inhibitor0.942
CYP450 2C19 inhibitorNon-inhibitor0.6909
CYP450 3A4 inhibitorNon-inhibitor0.8447
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8351
Ames testNon AMES toxic0.7287
CarcinogenicityNon-carcinogens0.9442
BiodegradationNot ready biodegradable0.9637
Rat acute toxicity2.4511 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9819
hERG inhibition (predictor II)Non-inhibitor0.6763
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-03k9-0709000000-b0a922c0009fee349863View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , PositiveNot Available
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
Taxonomy
DescriptionThis compound belongs to the class of chemical entities known as glutamic acid and derivatives. These are compounds containing glutamic acid or a derivative thereof resulting from reaction of glutamic acid at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
KingdomChemical entities
Super ClassOrganic compounds
ClassOrganic acids and derivatives
Sub ClassCarboxylic acids and derivatives
Direct ParentGlutamic acid and derivatives
Alternative ParentsN-acyl-alpha amino acids / Quinazolines / Thiophene carboxamides / 2-heteroaryl carboxamides / Dialkylarylamines / 2,5-disubstituted thiophenes / Hydroxypyrimidines / 2-aminothiophenes / Benzenoids / Dicarboxylic acids and derivatives
SubstituentsGlutamic acid or derivatives / N-acyl-alpha-amino acid / N-acyl-alpha amino acid or derivatives / Diazanaphthalene / Quinazoline / 2-heteroaryl carboxamide / Thiophene carboxamide / Thiophene carboxylic acid or derivatives / Dialkylarylamine / Hydroxypyrimidine
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsN-acyl-amino acid (CHEBI:5847 )

Targets

Details
1. Thymidylate synthase
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
Uniprot Name:
Thymidylate synthase
Molecular Weight:
35715.65 Da
References
  1. Yin MB, Guo B, Panadero A, Frank C, Wrzosek C, Slocum HK, Rustum YM: Cyclin E-cdk2 activation is associated with cell cycle arrest and inhibition of DNA replication induced by the thymidylate synthase inhibitor Tomudex. Exp Cell Res. 1999 Feb 25;247(1):189-99. [PubMed:10047461 ]
  2. Cao S, McGuire JJ, Rustum YM: Antitumor activity of ZD1694 (tomudex) against human head and neck cancer in nude mouse models: role of dosing schedule and plasma thymidine. Clin Cancer Res. 1999 Jul;5(7):1925-34. [PubMed:10430100 ]
  3. Ferguson PJ, Collins O, Dean NM, DeMoor J, Li CS, Vincent MD, Koropatnick J: Antisense down-regulation of thymidylate synthase to suppress growth and enhance cytotoxicity of 5-FUdR, 5-FU and Tomudex in HeLa cells. Br J Pharmacol. 1999 Aug;127(8):1777-86. [PubMed:10482907 ]
  4. Orlandi L, Bearzatto A, Abolafio G, De Marco C, Daidone MG, Zaffaroni N: Involvement of bcl-2 and p21waf1 proteins in response of human breast cancer cell clones to Tomudex. Br J Cancer. 1999 Sep;81(2):252-60. [PubMed:10496350 ]
  5. Grem JL, Sorensen JM, Cullen E, Takimoto CH, Steinberg SM, Chen AP, Hamilton JM, Arbuck SG, McAtee N, Lawrence D, Goldspiel B, Johnston PG, Allegra CJ: A Phase I study of raltitrexed, an antifolate thymidylate synthase inhibitor, in adult patients with advanced solid tumors. Clin Cancer Res. 1999 Sep;5(9):2381-91. [PubMed:10499608 ]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
  7. Yang Z, Waldman AS, Wyatt MD: DNA damage and homologous recombination signaling induced by thymidylate deprivation. Biochem Pharmacol. 2008 Oct 15;76(8):987-96. doi: 10.1016/j.bcp.2008.08.010. Epub 2008 Aug 19. [PubMed:18773878 ]
  8. Chen VJ, Bewley JR, Andis SL, Schultz RM, Iversen PW, Shih C, Mendelsohn LG, Seitz DE, Tonkinson JL: Cellular pharmacology of MTA: a correlation of MTA-induced cellular toxicity and in vitro enzyme inhibition with its effect on intracellular folate and nucleoside triphosphate pools in CCRF-CEM cells. Semin Oncol. 1999 Apr;26(2 Suppl 6):48-54. [PubMed:10598555 ]
  9. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [PubMed:10592235 ]
Details
2. Folylpolyglutamate synthase, mitochondrial
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
antagonist
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
Uniprot Name:
Folylpolyglutamate synthase, mitochondrial
Molecular Weight:
64608.53 Da
References
  1. Innocenti F, Ratain MJ: Update on pharmacogenetics in cancer chemotherapy. Eur J Cancer. 2002 Mar;38(5):639-44. [PubMed:11916544 ]
Drug created on June 13, 2005 07:24 / Updated on August 02, 2017 16:22