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)
Molecular Formula | C2H6O4S |
Molecular Weight | 126.132 |
Charge | 0 |
Count |
|
Stereochemistry | ACHIRAL |
Additional Stereochemistry | No |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Optical Activity | NONE |
Molecular Formula | C17H19N5O2 |
Molecular Weight | 325.3651 |
Charge | 0 |
Count |
|
Stereochemistry | ACHIRAL |
Additional Stereochemistry | No |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Optical Activity | NONE |
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 |
---|---|---|---|
Target ID: CHEMBL202 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23627352 |
3.0 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
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 |
---|---|---|
Activity of lipid-soluble inhibitors of dihydrofolate reductase against Pneumocystis carinii in culture and in a rat model of infection. | 1987 Sep |
|
Pneumocystis carinii dihydrofolate reductase used to screen potential antipneumocystis drugs. | 1991 Jul |
|
Evaluation of the effect of drugs on the cyst form of Toxoplasma gondii. | 1991 Jul |
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Inhibition of Pneumocystis dihydrofolate reductase by analogs of pyrimethamine, methotrexate and trimetrexate. | 1991 Nov-Dec |
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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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In vitro model to assess effect of antimicrobial agents on Encephalitozoon cuniculi. | 1994 Oct |
|
Novel 2,4-diamino-5-substituted-pyrrolo[2,3-d]pyrimidines as classical and nonclassical antifolate inhibitors of dihydrofolate reductases. | 1995 Jun 9 |
|
6-substituted 2,4-diamino-5-methylpyrido[2,3-d]pyrimidines as inhibitors of dihydrofolate reductases from Pneumocystis carinii and Toxoplasma gondii and as antitumor agents. | 1995 May 12 |
|
Lipophilic antifolates as agents against opportunistic infections. 1. Agents superior to trimetrexate and piritrexim against Toxoplasma gondii and Pneumocystis carinii in in vitro evaluations. | 1996 Mar 15 |
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2,4-Diamino-6,7-dihydro-5H-cyclopenta[d]pyrimidine analogues of trimethoprim as inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase. | 1998 Mar 12 |
|
Computer modeling studies of the structural role of NADPH binding to active site mutants of human dihydrofolate reductase in complex with piritrexim. | 2001 |
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Synthesis of 2,4-diamino-6-(thioarylmethyl)pyrido[2,3-d]pyrimidines as dihydrofolate reductase inhibitors. | 2001 Nov |
|
A novel method of synthesis of 2,4-diamino-6-arylmethylquinazolines using palladium(0)-catalyzed organozinc chemistry. | 2001 Nov 2 |
|
Inhibition of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductases by 2,4-diamino-5-[2-methoxy-5-(omega-carboxyalkyloxy)benzyl]pyrimidines: marked improvement in potency relative to trimethoprim and species selectivity relative to piritrexim. | 2002 Jan 3 |
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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 |
|
Synthesis of classical and nonclassical, partially restricted, linear, tricyclic 5-deaza antifolates. | 2002 Nov 7 |
|
QSAR studies on biological activity of piritrexim analogues against pc DHFR. | 2002 Sep |
|
Further studies on 2,4-diamino-5-(2',5'-disubstituted benzyl)pyrimidines as potent and selective inhibitors of dihydrofolate reductases from three major opportunistic pathogens of AIDS. | 2003 Apr 24 |
|
Synthesis of new 2,4-Diaminopyrido[2,3-d]pyrimidine and 2,4-Diaminopyrrolo[2,3-d]pyrimidine inhibitors of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductase. | 2003 Jan 2 |
|
Gemcitabine, Paclitaxel, and piritrexim: a phase I study. | 2003 Jun |
|
Separation and determination of the antitumor drug piritrexim by molecularly imprinted microspheres in high-performance liquid chromatography. | 2003 Sep |
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Structural variations of piritrexim, a lipophilic inhibitor of human dihydrofolate reductase: synthesis, antitumor activity and molecular modeling investigations. | 2004 Dec |
|
Accumulation of 5-phosphoribosyl-1-pyrophosphate in human CCRF-CEM leukaemia cells treated with antifolates. | 2004 Mar |
|
New 2,4-diamino-5-(2',5'-substituted benzyl)pyrimidines as potential drugs against opportunistic infections of AIDS and other immune disorders. Synthesis and species-dependent antifolate activity. | 2004 Mar 11 |
|
Design, synthesis, and computational affinity prediction of ester soft drugs as inhibitors of dihydrofolate reductase from Pneumocystis carinii. | 2004 May |
|
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 |
|
Phase I study of piritrexim and gemcitabine in patients with advanced solid tumors. | 2005 Dec |
|
Synthesis of the lipophilic antifolate piritrexim via a palladium(0)-catalyzed cross-coupling reaction. | 2005 Feb 18 |
|
Design, synthesis, and antifolate activity of new analogues of piritrexim and other diaminopyrimidine dihydrofolate reductase inhibitors with omega-carboxyalkoxy or omega-carboxy-1-alkynyl substitution in the side chain. | 2005 Jun 30 |
|
Mutant Gly482 and Thr482 ABCG2 mediate high-level resistance to lipophilic antifolates. | 2006 Dec |
|
Dihydrofolate reductase as a target for chemotherapy in parasites. | 2007 |
|
Vinflunine in the treatment of bladder cancer. | 2008 Dec |
|
Pulmonary complications of novel antineoplastic agents for solid tumors. | 2008 Feb |
|
Phase II open-label study of oral piritrexim in patients with advanced carcinoma of the urothelium who have experienced failure with standard chemotherapy. | 2008 Mar |
|
Anticancer agents against malaria: time to revisit? | 2010 Mar |
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.
Substance Class |
Chemical
Created
by
admin
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Edited
Fri Dec 15 18:37:20 GMT 2023
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Record UNII |
V77I71FH72
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Record Status |
Validated (UNII)
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Record Version |
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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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79483-69-5
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T-49
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V77I71FH72
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m8882
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351521
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CHEMBL7492
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C91407
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54368
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DBSALT002395
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DTXSID101000531
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