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
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)
| 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 |
DescriptionSources: http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2009/10/WC500006236.pdfCurator's Comment: Description was created based on several sources, including http://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=42223
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
Cmax
| 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 | Co-administered | 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 |
T1/2
| Value | Dose | Co-administered | 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 |
Funbound
| 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 |
PubMed
| Title | Date | PubMed |
|---|---|---|
| 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 |
|
| 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 |
|
| 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
| Substance Class |
Chemical
Created
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admin
on
Edited
Sat Dec 16 17:35:33 GMT 2023
by
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| Record UNII |
K75ZUN743Q
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| Record Status |
Validated (UNII)
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| Record Version |
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EU-Orphan Drug |
EU/3/03/165
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FDA ORPHAN DRUG |
148801
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NCI_THESAURUS |
C2021
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CHEMBL320775
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135400184
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C099178
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100000083585
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NOLATREXED
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C143088
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SUB09342MIG
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7683
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K75ZUN743Q
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147149-76-6
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m8029
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DB12912
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DTXSID3048281
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| Related Record | Type | Details | ||
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SALT/SOLVATE -> PARENT |
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TARGET -> INHIBITOR |
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ACTIVE MOIETY |
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