NOLATREXED

Investigational

Details

Stereochemistry	ACHIRAL
Molecular Formula	C14H12N4OS
Molecular Weight	284.336
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC1=C(SC2=CC=NC=C2)C3=C(C=C1)N=C(N)NC3=O

InChI

InChIKey=XHWRWCSCBDLOLM-UHFFFAOYSA-N

InChI=1S/C14H12N4OS/c1-8-2-3-10-11(13(19)18-14(15)17-10)12(8)20-9-4-6-16-7-5-9/h2-7H,1H3,(H3,15,17,18,19)

HIDE SMILES / InChI

Molecular Formula	C14H12N4OS
Molecular Weight	284.336
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2009/10/WC500006236.pdf
Curator's Comment: Description was created based on several sources, including http://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=42223

The dihydrochloride salt of nolatrexed, a water-soluble lipophilic quinazoline folate analog with antineoplastic activity. Nolatrexed occupies the folate binding site of thymidylate synthase, resulting in inhibition of thymidylate synthase activity and thymine nucleotide synthesis with subsequent inhibition of DNA replication, DNA damage, S-phase cell cycle arrest, and caspase-dependent apoptosis. This agent also exhibits radiosensitizing activity. Orphan designation of nolatrexed was granted in the Unites States of America for treatment of hepatocellular carcinoma.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Thymidylate synthase 31 Target ID: CHEMBL1952 Sources: http://www.apexbt.com/nolatrexed-ag-337.html	Inhibitor 8228		11.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Hepatocellular carcinoma 83 Sources: http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2009/10/WC500006236.pdf	Primary		Phase III 663	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
24 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9508200	1040 mg/m² 1 times / day multiple, intravenous dose: 1040 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		NOLATREXED plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
19.2 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9918208	250 mg/m² 4 times / day multiple, oral dose: 250 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:		NOLATREXED plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
107 mg × min/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9508200	904 mg/m² 1 times / day multiple, intravenous dose: 904 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	NOLATREXED plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
131 mg × min/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9508200	1040 mg/m² 1 times / day multiple, intravenous dose: 1040 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	NOLATREXED plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
3.1 μg × min/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9918208	250 mg/m² 4 times / day multiple, oral dose: 250 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	NOLATREXED plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
298 min EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9508200	904 mg/m² 1 times / day multiple, intravenous dose: 904 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	NOLATREXED plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
203 min EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9508200	1040 mg/m² 1 times / day multiple, intravenous dose: 1040 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	NOLATREXED plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
97 min EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9815922	1350 mg/m² single, intravenous dose: 1350 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered:	NOLATREXED plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
2.75% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9815922	1350 mg/m² single, intravenous dose: 1350 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered:		NOLATREXED plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P01CC92	https://www.1pchem.com/search?query=1P01CC92
AK Scientific	8186AH	https://aksci.com/item_detail.php?cat=8186AH
AK Scientific	O382	https://aksci.com/item_detail.php?cat=O382
Angene	AGN-PC-0JLG5J	http://www.angenechemical.com/productshow/AGN-PC-0JLG5J.html
ApexBio Technology	B5892	https://www.apexbt.com/catalogsearch/result/?q=B5892
Axon MedChem	2853	https://www.axonmedchem.com/product/2853
BOC Sciences	147149-76-6	http://www.bocsci.com/description.asp?cas=147149-76-6
BOC Sciences	152946-68-4	http://www.bocsci.com/description.asp?cas=152946-68-4
Chem Scene	CS-0028903	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0028903
Excenen	EX-A2112	http://www.excenen.com/searchresultlist.php?id=EX-A2112
Lab Network	LN01306589	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01306589
Lab Network	LN01806156	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01806156
Lab Seeker	SC-18884	http://www.labseeker.com/search.php?keywords=SC-18884&category=0
LabSeeker	SC-18884	http://www.labseeker.com/search.php?keywords=SC-18884&category=0
MedChem Express	HY-108474	https://www.medchemexpress.com/search.html?q=HY-108474&ft=&fa=&fp=
MolPort	MolPort-005-935-365	https://www.molport.com/shop/molecule-link/MolPort-005-935-365
MolPort	MolPort-016-638-439	https://www.molport.com/shop/molecule-link/MolPort-016-638-439
MolPort	MolPort-035-394-976	https://www.molport.com/shop/molecule-link/MolPort-035-394-976
MuseChem	R008557	https://www.musechem.com/product/R008557.html
MuseChem	R011020	https://www.musechem.com/product/R011020.html
PI Chemicals	PI-36644	http://www.pipharm.com/catalog_products/PI-36644.html
Ryan Scientific	RI-2	https://ryansci.com/products?q=RI-2&list_q=&search_type=exact
ShangHai Biochempartner	BCP02372	http://www.biochempartner.com/search_BCP02372
ShangHai Biochempartner	BCP12638	http://www.biochempartner.com/search_BCP12638
Tetrahedron	TS54748	http://www.thsci.com/search.do?q=TS54748
Tetrahedron	TS79378	http://www.thsci.com/search.do?q=TS79378
Toronto Research Chemicals	N635800	https://www.trc-canada.com/product-detail/?CatNum=N635800
eMolecules	2728791	https://orderbb.emolecules.com/search/#?query=2728791
eMolecules	300853761	https://orderbb.emolecules.com/search/#?query=300853761
eMolecules	45916648	https://orderbb.emolecules.com/search/#?query=45916648
eMolecules	64094759	https://orderbb.emolecules.com/search/#?query=64094759
eMolecules	8796923	https://orderbb.emolecules.com/search/#?query=8796923
eNovation Chemicals	D501905	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D501905&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-3223857505	https://mcule.com/MCULE-3223857505/
mcule	MCULE-8115720426	https://mcule.com/MCULE-8115720426/

PubMed

Title	Date	PubMed
Preclinical evaluation of locoregional delivery of radiolabeled iododeoxyuridine and thymidylate synthase inhibitor in a hepatoma model.	2001 Feb	11216535
A phase I study of nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children's Cancer Study Group Investigation.	2001 Jan 5	11139306
Result of two randomized trials comparing nolatrexed (Thymitaq) versus methotrexate in patients with recurrent head and neck cancer.	2001 Nov	11822760
[Effects of nolatrexed on thymidylate synthase protein expression].	2004 Aug	15321751
Serine/threonine protein phosphatase inhibition enhances the effect of thymidylate synthase inhibition.	2004 Mar	14648018
Nucleobase- and p-glycoprotein-mediated transport of AG337 in a Caco-2 cell culture model.	2004 May-Jun	15981922
Kinetics and ligand-binding preferences of Mycobacterium tuberculosis thymidylate synthases, ThyA and ThyX.	2008 May 21	18493582
Successful applications of computer aided drug discovery: moving drugs from concept to the clinic.	2010	19929824
Antifolate inhibitors of thymidylate synthase as anticancer drugs.	2010 Nov	20854257

Sample Use Guides

In Vivo Use Guide

Nolatrexed can be safely administered as an oral preparation at a dose of 800 mg/m2/day for 5 days.

Route of Administration: Oral

In Vitro Use Guide

In HT29 cells, exposure to nolatrexed (5 uM) for 24 h induced S-phase cell cycle arrest. In HCT116 cells, exposure to nolatrexed (5 lM) for 24 h also induced S-phase arrest with the cell population significantly increasing during this phase from 24% to 40%.

Substance Class	Chemical Created by `admin` on `Thu Jul 06 22:57:24 UTC 2023` Edited by `admin` on `Thu Jul 06 22:57:24 UTC 2023`
Record UNII	K75ZUN743Q
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

NOLATREXED

Official Name

English

NOLATREXED [MI]

Common Name

English

2-AMINO-6-METHYL-5-(4-PYRIDYLTHIO)-4(3H)-QUINAZOLINONE

Systematic Name

English

2-AMINO-6-METHYL-5-(4-PYRIDINYLTHIO)-4(1H)-QUINAZOLINONE

Systematic Name

English

NOLATREXED [MART.]

Common Name

English

4(1H)-QUINAZOLINONE, 2-AMINO-6-METHYL-5-(4-PYRIDINYLTHIO)-

Systematic Name

English

Nolatrexed [WHO-DD]

Common Name

English

2-AMINO-3,4-DIHYDRO-6-METHYL-4-OXO-5-(4-PYRIDYLTHIO)QUINAZOLINE

Systematic Name

English

nolatrexed [INN]

Common Name

English

2-AMINO-6-METHYL-5-(PYRIDIN-4-YLSULFANYL)-3H-QUINAZOLIN-4-ONE

Systematic Name

English

Classification Tree Code System Code

EU-Orphan Drug

EU/3/03/165