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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
Synonyms
SynonymLanguageCode
RaltitrexedNot AvailableNot Available
TomudexNot AvailableNot Available
ZD1694Not AvailableNot Available
SaltsNot Available
Brand names
NameCompany
TomudexAstraZeneca
Brand mixturesNot Available
CategoriesNot Available
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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganic Acids and Derivatives
ClassCarboxylic Acids and Derivatives
SubclassAmino Acids, Peptides, and Analogues
Direct parentN-acyl-alpha Amino Acids
Alternative parentsQuinazolines; Thiophene Carboxamides; Pyrimidones; Amino Fatty Acids; Dicarboxylic Acids and Derivatives; Aminothiophenes; Benzene and Substituted Derivatives; Secondary Carboxylic Acid Amides; Tertiary Amines; Polyols; Enolates; Carboxylic Acids; Polyamines
Substituentsquinazoline; thiophene carboxylic acid or derivative; thiophene carboxamide; pyrimidone; aminothiophene; benzene; pyrimidine; dicarboxylic acid derivative; thiophene; tertiary amine; secondary carboxylic acid amide; carboxamide group; polyol; enolate; polyamine; carboxylic acid; amine; organonitrogen compound
Classification descriptionThis compound belongs to the n-acyl-alpha amino acids. These are compounds containing an alpha amino acid which bears an acyl group at his terminal nitrogen atom.
Pharmacology
IndicationFor the treatment of malignant neoplasm of colon and rectum
PharmacodynamicsRaltitrexed 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 actionRaltitrexed 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.
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 life198 hours
ClearanceNot Available
ToxicitySide 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
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption - 0.6717
Blood Brain Barrier - 0.9044
Caco-2 permeable - 0.7873
P-glycoprotein substrate Substrate 0.7093
P-glycoprotein inhibitor I Non-inhibitor 0.9214
P-glycoprotein inhibitor II Non-inhibitor 0.9588
Renal organic cation transporter Non-inhibitor 0.8799
CYP450 2C9 substrate Non-substrate 0.7133
CYP450 2D6 substrate Non-substrate 0.8077
CYP450 3A4 substrate Substrate 0.6032
CYP450 1A2 substrate Non-inhibitor 0.7801
CYP450 2C9 substrate Non-inhibitor 0.5435
CYP450 2D6 substrate Non-inhibitor 0.942
CYP450 2C19 substrate Non-inhibitor 0.6909
CYP450 3A4 substrate Non-inhibitor 0.8447
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8351
Ames test Non AMES toxic 0.7287
Carcinogenicity Non-carcinogens 0.9442
Biodegradation Not ready biodegradable 0.9637
Rat acute toxicity 2.4511 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9819
hERG inhibition (predictor II) Non-inhibitor 0.6763
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Powder, for solutionIntravenous
PricesNot Available
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point180-184 °CNot Available
water solubilitysolubleNot Available
logP-1.2Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0181ALOGPS
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
Spectra
SpectraNot Available
References
Synthesis Reference

DrugSyn.org

US4992550
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD01064
KEGG CompoundC11372
PubChem Compound104758
PubChem Substance46504880
ChemSpider94568
BindingDB18795
Therapeutic Targets DatabaseDAP000759
PharmGKBPA131625240
HETD16
Drug Product Database2229566
WikipediaRaltitrexed
ATC CodesL01BA03
AHFS Codes
  • 92:00.00
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(57 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. Thymidylate synthase

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Thymidylate synthase P04818 Details

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
  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
  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
  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
  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
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  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. Epub 2008 Aug 19. Pubmed
  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
  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

2. Folylpolyglutamate synthase, mitochondrial

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

Name UniProt ID Details
Folylpolyglutamate synthase, mitochondrial Q05932 Details

References:

  1. Innocenti F, Ratain MJ: Update on pharmacogenetics in cancer chemotherapy. Eur J Cancer. 2002 Mar;38(5):639-44. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on October 08, 2013 14:25