Details
Stereochemistry | ACHIRAL |
Molecular Formula | C17H19N5O2.C2H6O4S |
Molecular Weight | 451.497 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
OCCS(O)(=O)=O.COC1=CC(CC2=C(C)C3=C(N=C2)N=C(N)N=C3N)=C(OC)C=C1
InChI
InChIKey=IOEMETRLOWNXGW-UHFFFAOYSA-N
InChI=1S/C17H19N5O2.C2H6O4S/c1-9-11(6-10-7-12(23-2)4-5-13(10)24-3)8-20-16-14(9)15(18)21-17(19)22-16;3-1-2-7(4,5)6/h4-5,7-8H,6H2,1-3H3,(H4,18,19,20,21,22);3H,1-2H2,(H,4,5,6)
DescriptionSources: https://www.ncbi.nlm.nih.gov/pubmed/8924375Curator's Comment: description was created based on several sources, including
https://www.drugbank.ca/drugs/DB03695 | https://www.ncbi.nlm.nih.gov/pubmed/18501080 | https://www.ncbi.nlm.nih.gov/pubmed/9220296 | https://www.ncbi.nlm.nih.gov/pubmed/17346178
Sources: https://www.ncbi.nlm.nih.gov/pubmed/8924375
Curator's Comment: description was created based on several sources, including
https://www.drugbank.ca/drugs/DB03695 | https://www.ncbi.nlm.nih.gov/pubmed/18501080 | https://www.ncbi.nlm.nih.gov/pubmed/9220296 | https://www.ncbi.nlm.nih.gov/pubmed/17346178
Piritrexim is a synthetic antifolate agent with antiparasitic, antipsoriatic and antitumor properties. Piritrexim inhibits the enzyme dihydrofolate reductase, thereby disrupting folate metabolism and DNA synthesis and cell division. A theoretical advantage of piritrexim over trimetrexate is a lack of any known effects on histamine metabolism, which may lower the risk of hypersensitivity reactions. Piritrexim is a nonclassical antifolate for antitumor and parasitic chemotherapy that passively diffuses into cells and hence do not have to depend on folylpoly-gamma-glutamate synthetase or the reduced folate carrier. Because piritrexim is not a substrate for polyglutamation, the drug is not selectively retained within cells for prolonged periods. Piritrexim has a reliably high oral bioavailability of about 75%, which has led to its development as an oral lipophilic antifolate. Most commonly, it has been administered in oral daily doses of 75 to 150 mg bid or tid every 5 days, with cycles repeated every 3 weeks. Oral absorption is rapid, with peak plasma levels appearing at 1.5 hours after ingestion. Elimination occurs primarily via hepatic metabolism of the drug to active metabolites, and the terminal half-life of the parent compound is about 1.5 to 4.5 hours. Single-agent oral piritrexim has clinical activity in melanoma, urothelial cancers, and head and neck cancers. Tolerable combinations of piritrexim with cisplatin, fluorouracil, and leucovorin have been tested, with promising results achieved in head and neck cancer. An interesting attempt to alternate piritrexim with methotrexate did not have any greater activity than methotrexate alone.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
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Target ID: CHEMBL202 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23627352 |
3.0 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
3.3 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1732038 |
25 mg/m² 3 times / day multiple, oral dose: 25 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: |
PIRITREXIM plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED |
|
3.3 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1732038 |
20 mg/m² 3 times / day multiple, oral dose: 20 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: |
PIRITREXIM plasma | Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: FED |
|
2.3 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1732038 |
15 mg/m² 3 times / day multiple, oral dose: 15 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: |
PIRITREXIM plasma | Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: FED |
|
2.3 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1732038 |
10 mg/m² 3 times / day multiple, oral dose: 10 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: |
PIRITREXIM plasma | Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: FED |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
13.3 μM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1732038 |
25 mg/m² 3 times / day multiple, oral dose: 25 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: |
PIRITREXIM plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED |
|
12.4 μM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1732038 |
20 mg/m² 3 times / day multiple, oral dose: 20 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: |
PIRITREXIM plasma | Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: FED |
|
8 μM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1732038 |
15 mg/m² 3 times / day multiple, oral dose: 15 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: |
PIRITREXIM plasma | Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: FED |
|
9.3 μM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1732038 |
10 mg/m² 3 times / day multiple, oral dose: 10 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: |
PIRITREXIM plasma | Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: FED |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
2.11 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1732038 |
25 mg/m² 3 times / day multiple, oral dose: 25 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: |
PIRITREXIM plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED |
|
2.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1732038 |
20 mg/m² 3 times / day multiple, oral dose: 20 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: |
PIRITREXIM plasma | Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: FED |
|
2.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1732038 |
15 mg/m² 3 times / day multiple, oral dose: 15 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: |
PIRITREXIM plasma | Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: FED |
|
2.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1732038 |
10 mg/m² 3 times / day multiple, oral dose: 10 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: |
PIRITREXIM plasma | Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: FED |
Doses
Dose | Population | Adverse events |
---|---|---|
25 mg 12 times / week multiple, oral (unknown) Studied dose Dose: 25 mg, 12 times / week Route: oral Route: multiple Dose: 25 mg, 12 times / week Sources: |
unhealthy n = 1 Health Status: unhealthy Condition: transitional cell carcinoma Sex: M Food Status: UNKNOWN Population Size: 1 Sources: |
Disc. AE: Pulmonary toxicity... AEs leading to discontinuation/dose reduction: Pulmonary toxicity (1 pt) Sources: |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Pulmonary toxicity | 1 pt Disc. AE |
25 mg 12 times / week multiple, oral (unknown) Studied dose Dose: 25 mg, 12 times / week Route: oral Route: multiple Dose: 25 mg, 12 times / week Sources: |
unhealthy n = 1 Health Status: unhealthy Condition: transitional cell carcinoma Sex: M Food Status: UNKNOWN Population Size: 1 Sources: |
PubMed
Title | Date | PubMed |
---|---|---|
In vivo activity of piritrexim [corrected] against Toxoplasma gondii. | 1987 Nov |
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Pneumocystis carinii dihydrofolate reductase used to screen potential antipneumocystis drugs. | 1991 Jul |
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2,4-Diamino-5-chloroquinazoline analogues of trimetrexate and piritrexim: synthesis and antifolate activity. | 1994 Dec 23 |
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New drug developments for opportunistic infections in immunosuppressed patients: Pneumocystis carinii. | 1995 Nov 24 |
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Synthesis of 2,4-diamino-6-(thioarylmethyl)pyrido[2,3-d]pyrimidines as dihydrofolate reductase inhibitors. | 2001 Nov |
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Atomic structures of human dihydrofolate reductase complexed with NADPH and two lipophilic antifolates at 1.09 a and 1.05 a resolution. | 2002 Jul 12 |
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Piritrexim in advanced, refractory carcinoma of the urothelium (E3896): a phase II trial of the Eastern Cooperative Oncology Group. | 2002 Nov |
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Separation and determination of the antitumor drug piritrexim by molecularly imprinted microspheres in high-performance liquid chromatography. | 2003 Sep |
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Accumulation of 5-phosphoribosyl-1-pyrophosphate in human CCRF-CEM leukaemia cells treated with antifolates. | 2004 Mar |
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Synthesis of 2,4-diamino-6-[2'-O-(omega-carboxyalkyl)oxydibenz[b,f]azepin-5-yl]methylpteridines as potent and selective inhibitors of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductase. | 2004 May 6 |
|
Cancer chemotherapy: targeting folic acid synthesis. | 2010 Nov 19 |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/18501080
Patients received piritrexim orally at 25 mg 3 times daily (every 8 hours regularly) for 5 consecutive days each week for 3 weeks, followed by a 1-week rest period.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/8632413
Cell lines A549 (human non-small-cell lung carcinoma), Daoy (human medulloblastoma), U87MG and U373MG (human glioblastomas), HCT-8 (human ileocecal adenocarcinoma), 143B(TK-) (thymidine kinase-deficient human osteosarcoma), Vero (African green monkey kidney), and P388D1 (mouse lymphoid neoplasm) and mouse L cells were used for activity evaluation. Cytotoxicity measurements were carried out in 96-well microtiter plates using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) dye reduction assay for suspension cultures or the sulforhodamine B assay for monolayer cultures.
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NCI_THESAURUS |
C511
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NCI_THESAURUS |
C2153
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FDA ORPHAN DRUG |
29188
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ACTIVE MOIETY
PARENT (SALT/SOLVATE)
SUBSTANCE RECORD