Raltitrexed - DrugBank

ID Pharmacology Interactions References Trials Economics Properties Spectra Taxonomy

Targets (2)

Targets (2)Biointeractions (2)

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

MOL SDF 3D-SDF PDB SMILES InChI View 3D Structure

Synonyms

Raltitrexed

Tomudex

External IDs

ZD 1694 / ZD-1694 / ZD1694

Product Ingredients

Not Available

Approved Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Tomudex	Powder, for solution	2 mg	Intravenous	Hospira, Inc.	1996-11-18	Not applicable	Canada

Approved Generic Prescription Products

Not Available

Approved Over the Counter Products

Not Available

Unapproved/Other Products

Not Available

International Brands

Not Available

Brand mixtures

Not Available

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[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.

Target	Kind	Pharmacological action	Actions	Organism	UniProt ID
Thymidylate synthase	Protein	yes	inhibitor	Human	P04818	details
Folylpolyglutamate synthase, mitochondrial	Protein	unknown	antagonist	Human	Q05932	details

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
BCG vaccine	The therapeutic efficacy of Bcg can be decreased when used in combination with Raltitrexed.	Investigational
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
Deslanoside	Deslanoside may decrease the cardiotoxic activities of Raltitrexed.	Approved
Digitoxin	Digitoxin may decrease the cardiotoxic activities of Raltitrexed.	Approved
Digoxin	Digoxin 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
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
Levomefolic acid	The therapeutic efficacy of Raltitrexed can be decreased when used in combination with Levomefolic acid.	Approved
Metamizole	The risk or severity of adverse effects can be increased when Metamizole is combined with Raltitrexed.	Withdrawn
Oleandrin	Anvirzel may decrease the cardiotoxic activities of Raltitrexed.	Experimental
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
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

Resource	Link
Human Metabolome Database (HMDB)	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
Drug Product Database	11098
Wikipedia	Raltitrexed

ATC Codes

L01BA03 — Raltitrexed

AHFS Codes

92:00.00

PDB Entries

Not Available

FDA label

Not Available

MSDS

Download (57 KB)

Clinical Trials

Phase	Status	Purpose	Conditions	Count
1	Completed	Treatment	Colorectal Cancers	1
1	Completed	Treatment	Neoplasms	1
1	Completed	Treatment	Recurrent Childhood Acute Lymphoblastic Leukemia / Recurrent Childhood Acute Myeloid Leukemia	1
1	Completed	Treatment	Unspecified Adult Solid Tumor, Protocol Specific	2
2	Active Not Recruiting	Treatment	Rectal Carcinoma	1
2	Completed	Treatment	Adenocarcinoma of Colon / Adenocarcinoma of Rectum / Metastatic Disease	1
2	Completed	Treatment	Inoperable or Recurrent Rectal Cancer	1
2	Completed	Treatment	Mesothelioma, Malignant	1
2	Completed	Treatment	Rectal Neoplasms	1
2	Not Yet Recruiting	Treatment	Metastatic Colon Cancer	1
2	Recruiting	Treatment	Colorectal Cancers	1
2	Recruiting	Treatment	Colorectal Cancers / Hepatic Metastases	1
2	Recruiting	Treatment	Gastroesophageal Junction Adenocarcinoma / Malignant Neoplasm of Stomach	1
2	Recruiting	Treatment	Nasopharyngeal Carcinoma	1
2	Recruiting	Treatment	Rectal Neoplasms Malignant	1
2	Unknown Status	Treatment	Carcinoma, Colorectal	1
2	Unknown Status	Treatment	Inoperable Esophageal Cancer Stage I-III	1
2, 3	Completed	Treatment	Colorectal Cancers	1
3	Completed	Treatment	Mesothelioma, Malignant	1
3	Recruiting	Treatment	Head and Neck Squamous Cell Cancer	1
3	Unknown Status	Treatment	Colorectal Cancers	1
4	Not Yet Recruiting	Treatment	Head and Neck Squamous Cell Carcinoma (HNSCC)	1
4	Recruiting	Treatment	Colon Cancer Liver Metastasis	1
4	Recruiting	Treatment	Metastatic Colorectal Cancers	1

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

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum Type	Description	Splash Key
LC-MS/MS	LC-MS/MS Spectrum - , positive	splash10-03k9-0709000000-b0a922c0009fee349863	View in MoNA
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	Not Available
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	Not Available
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	Not Available
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	Not Available
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	Not Available
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	Not Available

Taxonomy

Description

This 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.

Kingdom

Chemical entities

Super Class

Organic compounds

Class

Organic acids and derivatives

Sub Class

Carboxylic acids and derivatives

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

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

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
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 ]

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
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 July 18, 2017 16:47

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Structure for DB00293 (Raltitrexed)

Targets

References

References