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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 of NOLATREXED

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
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.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
11.0 nM [Ki]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
24 μg/mL
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
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

AUC

ValueDoseCo-administeredAnalytePopulation
107 mg × min/mL
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
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
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
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
298 min
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
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
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
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
2.75%
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

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
Characterization and drug sensitivity of four newly established colon adenocarcinoma cell lines to antifolate inhibitors of thymidylate synthase.
2001
Preclinical evaluation of locoregional delivery of radiolabeled iododeoxyuridine and thymidylate synthase inhibitor in a hepatoma model.
2001 Feb
A phase I study of nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children's Cancer Study Group Investigation.
2001 Jan 5
Thymitaq (Zarix).
2001 May
Thymidylate synthase pharmacogenetics in colorectal cancer.
2001 Nov
Result of two randomized trials comparing nolatrexed (Thymitaq) versus methotrexate in patients with recurrent head and neck cancer.
2001 Nov
Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK.
2003 Aug 4
Thymidylate synthase inhibitors as anticancer agents: from bench to bedside.
2003 Jul
Novel antifolate drugs.
2003 Mar
Nonsteroidal anti-inflammatory drugs in colorectal cancer: from prevention to therapy.
2003 Mar 24
2-[11C]thymidine positron emission tomography as an indicator of thymidylate synthase inhibition in patients treated with AG337.
2003 May 7
Prospective randomised phase II study of gemcitabine at standard or fixed dose rate schedule in unresectable hepatocellular carcinoma.
2003 Nov 17
[Effects of nolatrexed on thymidylate synthase protein expression].
2004 Aug
Phase II study of viscum fraxini-2 in patients with advanced hepatocellular carcinoma.
2004 Jan 12
Serine/threonine protein phosphatase inhibition enhances the effect of thymidylate synthase inhibition.
2004 Mar
Nucleobase- and p-glycoprotein-mediated transport of AG337 in a Caco-2 cell culture model.
2004 May-Jun
Mutant Gly482 and Thr482 ABCG2 mediate high-level resistance to lipophilic antifolates.
2006 Dec
Low folate conditions may enhance the interaction of trifluorothymidine with antifolates in colon cancer cells.
2006 Jan
Elevation of radiolabelled thymidine uptake in RIF-1 fibrosarcoma and HT29 colon adenocarcinoma cells after treatment with thymidylate synthase inhibitors.
2006 Sep
Phase II trial of nolatrexed dihydrochloride [Thymitaq, AG 337] in patients with advanced hepatocellular carcinoma.
2007 Feb
Phase III randomized controlled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or doxorubicin.
2007 Jul 20
Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels.
2007 Mar 12
Recent advances in classical and non-classical antifolates as antitumor and antiopportunistic infection agents: part I.
2007 Sep
Recent advances in classical and non-classical antifolates as antitumor and antiopportunistic infection agents: Part II.
2008 Feb
[Preparation of long-circulating nolatrexed dihydrochloride liposomes and its antitumor activity].
2008 Mar
Kinetics and ligand-binding preferences of Mycobacterium tuberculosis thymidylate synthases, ThyA and ThyX.
2008 May 21
[Measurement of plasma concentration and bioavailability of nolatrexed dihydrochloride in mice].
2008 Nov
Successful applications of computer aided drug discovery: moving drugs from concept to the clinic.
2010
Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study.
2010 Feb
Antifolate inhibitors of thymidylate synthase as anticancer drugs.
2010 Nov

Sample Use Guides

In Vivo Use Guide
Curator's Comment: Can also be administered at a dose of 500 mg m(-2) day(-1) as a 120-h continuous intravenous infusion in combination with paclitaxel. http://www.ncbi.nlm.nih.gov/pubmed/10789718
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 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 Sat Dec 16 17:35:33 GMT 2023
Edited
by admin
on Sat Dec 16 17:35:33 GMT 2023
Record UNII
K75ZUN743Q
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
NOLATREXED
INN   MART.   MI   WHO-DD  
INN  
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
Created by admin on Sat Dec 16 17:35:33 GMT 2023 , Edited by admin on Sat Dec 16 17:35:33 GMT 2023
FDA ORPHAN DRUG 148801
Created by admin on Sat Dec 16 17:35:33 GMT 2023 , Edited by admin on Sat Dec 16 17:35:33 GMT 2023
NCI_THESAURUS C2021
Created by admin on Sat Dec 16 17:35:34 GMT 2023 , Edited by admin on Sat Dec 16 17:35:34 GMT 2023
Code System Code Type Description
ChEMBL
CHEMBL320775
Created by admin on Sat Dec 16 17:35:33 GMT 2023 , Edited by admin on Sat Dec 16 17:35:33 GMT 2023
PRIMARY
PUBCHEM
135400184
Created by admin on Sat Dec 16 17:35:34 GMT 2023 , Edited by admin on Sat Dec 16 17:35:34 GMT 2023
PRIMARY
MESH
C099178
Created by admin on Sat Dec 16 17:35:33 GMT 2023 , Edited by admin on Sat Dec 16 17:35:33 GMT 2023
PRIMARY
SMS_ID
100000083585
Created by admin on Sat Dec 16 17:35:34 GMT 2023 , Edited by admin on Sat Dec 16 17:35:34 GMT 2023
PRIMARY
WIKIPEDIA
NOLATREXED
Created by admin on Sat Dec 16 17:35:34 GMT 2023 , Edited by admin on Sat Dec 16 17:35:34 GMT 2023
PRIMARY
NCI_THESAURUS
C143088
Created by admin on Sat Dec 16 17:35:33 GMT 2023 , Edited by admin on Sat Dec 16 17:35:33 GMT 2023
PRIMARY
EVMPD
SUB09342MIG
Created by admin on Sat Dec 16 17:35:33 GMT 2023 , Edited by admin on Sat Dec 16 17:35:33 GMT 2023
PRIMARY
INN
7683
Created by admin on Sat Dec 16 17:35:33 GMT 2023 , Edited by admin on Sat Dec 16 17:35:33 GMT 2023
PRIMARY
FDA UNII
K75ZUN743Q
Created by admin on Sat Dec 16 17:35:33 GMT 2023 , Edited by admin on Sat Dec 16 17:35:33 GMT 2023
PRIMARY
CAS
147149-76-6
Created by admin on Sat Dec 16 17:35:33 GMT 2023 , Edited by admin on Sat Dec 16 17:35:33 GMT 2023
PRIMARY
MERCK INDEX
m8029
Created by admin on Sat Dec 16 17:35:33 GMT 2023 , Edited by admin on Sat Dec 16 17:35:33 GMT 2023
PRIMARY Merck Index
DRUG BANK
DB12912
Created by admin on Sat Dec 16 17:35:33 GMT 2023 , Edited by admin on Sat Dec 16 17:35:33 GMT 2023
PRIMARY
EPA CompTox
DTXSID3048281
Created by admin on Sat Dec 16 17:35:33 GMT 2023 , Edited by admin on Sat Dec 16 17:35:33 GMT 2023
PRIMARY
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