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Details

Stereochemistry ACHIRAL
Molecular Formula C14H12N4OS.2ClH
Molecular Weight 357.258
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of NOLATREXED DIHYDROCHLORIDE

SMILES

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

InChI

InChIKey=PJKVJJYMWOCLIJ-UHFFFAOYSA-N
InChI=1S/C14H12N4OS.2ClH/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);2*1H

HIDE SMILES / InChI

Molecular Formula ClH
Molecular Weight 36.461
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

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
[Effects of nolatrexed on thymidylate synthase protein expression].
2004 Aug
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
Phase II trial of nolatrexed dihydrochloride [Thymitaq, AG 337] in patients with advanced hepatocellular carcinoma.
2007 Feb
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 II.
2008 Feb
[Preparation of long-circulating nolatrexed dihydrochloride liposomes and its antitumor activity].
2008 Mar
[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
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 Thu Jul 06 01:11:14 UTC 2023
Edited
by admin
on Thu Jul 06 01:11:14 UTC 2023
Record UNII
1XA69O733O
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
NOLATREXED DIHYDROCHLORIDE
MI  
Common Name English
NOLATREXED DIHYDROCHLORIDE [MI]
Common Name English
2-AMINO-3,4-DIHYDRO-6-METHYL-4-OXO-5-(4-PYRIDYLTHIO)-QUINAZOLINE DIHYDROCHLORIDE
Systematic Name English
AG-337
Code English
4(1H)-QUINAZOLINONE, 2-AMINO-6-METHYL-5-(4-PYRIDINYLTHIO)-, HYDROCHLORIDE (1:2)
Systematic Name English
AG 337
Code English
4(1H)-QUINAZOLINONE, 2-AMINO-6-METHYL-5-(4-PYRIDINYLTHIO)-, DIHYDROCHLORIDE
Common Name English
THYMITAQ
Brand Name English
Classification Tree Code System Code
NCI_THESAURUS C2021
Created by admin on Thu Jul 06 01:11:14 UTC 2023 , Edited by admin on Thu Jul 06 01:11:14 UTC 2023
NCI_THESAURUS C511
Created by admin on Thu Jul 06 01:11:14 UTC 2023 , Edited by admin on Thu Jul 06 01:11:14 UTC 2023
Code System Code Type Description
NCI_THESAURUS
C1577
Created by admin on Thu Jul 06 01:11:14 UTC 2023 , Edited by admin on Thu Jul 06 01:11:14 UTC 2023
PRIMARY
PUBCHEM
135409535
Created by admin on Thu Jul 06 01:11:14 UTC 2023 , Edited by admin on Thu Jul 06 01:11:14 UTC 2023
PRIMARY
MERCK INDEX
M8029
Created by admin on Thu Jul 06 01:11:14 UTC 2023 , Edited by admin on Thu Jul 06 01:11:14 UTC 2023
PRIMARY Merck Index
EPA CompTox
DTXSID4046810
Created by admin on Thu Jul 06 01:11:14 UTC 2023 , Edited by admin on Thu Jul 06 01:11:14 UTC 2023
PRIMARY
EVMPD
SUB33221
Created by admin on Thu Jul 06 01:11:14 UTC 2023 , Edited by admin on Thu Jul 06 01:11:14 UTC 2023
PRIMARY
SMS_ID
100000126325
Created by admin on Thu Jul 06 01:11:14 UTC 2023 , Edited by admin on Thu Jul 06 01:11:14 UTC 2023
PRIMARY
CAS
152946-68-4
Created by admin on Thu Jul 06 01:11:14 UTC 2023 , Edited by admin on Thu Jul 06 01:11:14 UTC 2023
PRIMARY
FDA UNII
1XA69O733O
Created by admin on Thu Jul 06 01:11:14 UTC 2023 , Edited by admin on Thu Jul 06 01:11:14 UTC 2023
PRIMARY
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ACTIVE MOIETY