Identification

Name
Raltitrexed
Accession Number
DB00293  (APRD00430, EXPT01092)
Type
Small Molecule
Groups
Approved, 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
Synonyms
  • Raltitrexed
External IDs
ZD 1694 / ZD-1694 / ZD1694
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
TomudexPowder, for solution2 mgIntravenousPfizer1996-11-18Not applicableCanada
International/Other Brands
Tomudex
Categories
UNII
FCB9EGG971
CAS number
112887-68-0
Weight
Average: 458.488
Monoisotopic: 458.126005146
Chemical Formula
C21H22N4O6S
InChI Key
IVTVGDXNLFLDRM-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[[email protected]@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.

TargetActionsOrganism
AThymidylate synthase
inhibitor
Human
UFolylpolyglutamate synthase, mitochondrial
antagonist
Human
Absorption
Not Available
Volume of distribution
Not 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 elimination
Not Available
Half life

198 hours

Clearance
Not 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
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Raltitrexed.Approved
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Raltitrexed.Experimental
BCG vaccineThe therapeutic efficacy of BCG vaccine 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
CymarinCymarin may decrease the cardiotoxic activities of Raltitrexed.Experimental
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
GitoformateGitoformate may decrease the cardiotoxic activities of Raltitrexed.Experimental
Lanatoside CLanatoside C may decrease the cardiotoxic activities of Raltitrexed.Experimental
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
MetildigoxinMetildigoxin may decrease the cardiotoxic activities of Raltitrexed.Experimental
OleandrinOleandrin 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
PeruvosidePeruvoside may decrease the cardiotoxic activities of Raltitrexed.Experimental
ProscillaridinProscillaridin may decrease the cardiotoxic activities of Raltitrexed.Experimental
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Raltitrexed.Approved, Investigational
Food Interactions
Not Available

References

Synthesis Reference
US4992550
General References
Not Available
External Links
Human Metabolome Database
HMDB14438
KEGG Drug
D01064
KEGG Compound
C11372
PubChem Compound
104758
PubChem Substance
46504880
ChemSpider
94568
BindingDB
18795
ChEBI
5847
ChEMBL
CHEMBL225071
Therapeutic Targets Database
DAP000759
PharmGKB
PA131625240
HET
D16
Wikipedia
Raltitrexed
ATC Codes
L01BA03 — Raltitrexed
PDB Entries
1hvy / 1i00 / 1rts / 2kce / 2tsr / 3nrr / 4eb4 / 4fox / 4gtb / 4iqq
show 3 more
MSDS
Download (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
2RecruitingTreatmentAdenocarcinomas of the Gastroesophageal Junction / Malignant Neoplasm of Stomach1
2RecruitingTreatmentColorectal Cancers1
2RecruitingTreatmentColorectal Cancers / Hepatic Metastases1
2RecruitingTreatmentMetastatic Colon Cancer1
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

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Powder, for solutionIntravenous2 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
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
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
MS/MS Spectrum - , positiveLC-MS/MSsplash10-03k9-0709000000-b0a922c0009fee349863

Taxonomy

Description
This compound belongs to the class of organic compounds 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.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Glutamic acid and derivatives
Alternative Parents
N-acyl-alpha amino acids / Quinazolines / Thiophene carboxamides / 2-heteroaryl carboxamides / Dialkylarylamines / 2,5-disubstituted thiophenes / Hydroxypyrimidines / 2-aminothiophenes / Benzenoids / Dicarboxylic acids and derivatives
show 8 more
Substituents
Glutamic 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
show 21 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
N-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]
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 substrate...
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 October 02, 2017 04:34