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IdentificationPharmacologyInteractionsReferencesTrialsEconomicsPropertiesSpectraTaxonomyRaltitrexed
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
Structure for DB00293 (Raltitrexed)
- Synonyms
- Raltitrexed
- External IDs
- ZD 1694 / ZD-1694 / ZD1694
- Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Tomudex Powder, for solution 2 mg Intravenous Pfizer 1996-11-18 Not applicable Canada 
- 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.
Target Actions Organism AThymidylate synthase inhibitorHuman UFolylpolyglutamate synthase, mitochondrial antagonistHuman - 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
Drug Interaction Drug group Acetyldigitoxin Acetyldigitoxin may decrease the cardiotoxic activities of Raltitrexed. Approved Acetyldigoxin Acetyldigoxin may decrease the cardiotoxic activities of Raltitrexed. Experimental Ancestim The risk or severity of cytotoxicity can be increased when Ancestim is combined with Raltitrexed. Approved, Investigational, Withdrawn Bevacizumab Bevacizumab may increase the cardiotoxic activities of Raltitrexed. Approved, Investigational Cabazitaxel The risk or severity of adverse effects can be increased when Cabazitaxel is combined with Raltitrexed. Approved Clozapine The risk or severity of adverse effects can be increased when Raltitrexed is combined with Clozapine. Approved Cyclophosphamide Cyclophosphamide may increase the cardiotoxic activities of Raltitrexed. Approved, Investigational Cymarin Cymarin may decrease the cardiotoxic activities of Raltitrexed. Experimental Deslanoside Deslanoside may decrease the cardiotoxic activities of Raltitrexed. Approved Digitoxin Digitoxin may decrease the cardiotoxic activities of Raltitrexed. Approved, Investigational Digoxin Digoxin may decrease the cardiotoxic activities of Raltitrexed. Approved Digoxin Immune Fab (Ovine) Digoxin Immune Fab (Ovine) may decrease the cardiotoxic activities of Raltitrexed. Approved Docetaxel The risk or severity of adverse effects can be increased when Docetaxel is combined with Raltitrexed. Approved, Investigational Folic Acid The therapeutic efficacy of Raltitrexed can be decreased when used in combination with Folic Acid. Approved, Nutraceutical, Vet Approved Gitoformate Gitoformate may decrease the cardiotoxic activities of Raltitrexed. Experimental Lanatoside C Lanatoside C may decrease the cardiotoxic activities of Raltitrexed. Experimental Leucovorin The therapeutic efficacy of Raltitrexed can be decreased when used in combination with Leucovorin. Approved Levoleucovorin The therapeutic efficacy of Raltitrexed can be decreased when used in combination with Levoleucovorin. Approved, Investigational Levomefolic acid The therapeutic efficacy of Raltitrexed can be decreased when used in combination with Levomefolic acid. Approved, Investigational Metamizole The risk or severity of myelosuppression can be increased when Metamizole is combined with Raltitrexed. Approved, Investigational, Withdrawn Metildigoxin Metildigoxin may decrease the cardiotoxic activities of Raltitrexed. Experimental Oleandrin Oleandrin may decrease the cardiotoxic activities of Raltitrexed. Experimental, Investigational Ouabain Ouabain may decrease the cardiotoxic activities of Raltitrexed. Approved Paclitaxel The risk or severity of adverse effects can be increased when Paclitaxel is combined with Raltitrexed. Approved, Vet Approved Peruvoside Peruvoside may decrease the cardiotoxic activities of Raltitrexed. Experimental Proscillaridin Proscillaridin may decrease the cardiotoxic activities of Raltitrexed. Experimental Trastuzumab Trastuzumab 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
- HMDB0014438
- 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
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage forms
Form Route Strength Powder, for solution Intravenous 2 mg - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 180-184 °C Not Available water solubility soluble Not Available logP -1.2 Not Available - Predicted Properties
Property Value Source Water Solubility 0.0181 mg/mL ALOGPS logP 1.65 ALOGPS logP 1.97 ChemAxon logS -4.4 ALOGPS pKa (Strongest Acidic) 3.72 ChemAxon pKa (Strongest Basic) -0.46 ChemAxon Physiological Charge -2 ChemAxon Hydrogen Acceptor Count 9 ChemAxon Hydrogen Donor Count 4 ChemAxon Polar Surface Area 148.4 Å2 ChemAxon Rotatable Bond Count 9 ChemAxon Refractivity 117.39 m3·mol-1 ChemAxon Polarizability 45.55 Å3 ChemAxon Number of Rings 3 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter Yes ChemAxon Veber's Rule No ChemAxon MDDR-like Rule Yes ChemAxon - 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 inhibitor Non-inhibitor 0.5435 CYP450 2D6 inhibitor Non-inhibitor 0.942 CYP450 2C19 inhibitor Non-inhibitor 0.6909 CYP450 3A4 inhibitor 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
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS Not Available Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available MS/MS Spectrum - , positive LC-MS/MS splash10-03k9-0709000000-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
- 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
- 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]
- 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]
- 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]
- 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]
- 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]
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
- 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]
- 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]
- 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
- 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 March 02, 2018 01:55