TRIMETREXATE

US Previously Marketed

First approved in 1993

Details

Stereochemistry	ACHIRAL
Molecular Formula	C19H23N5O3
Molecular Weight	369.4176
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

COC1=CC(NCC2=C(C)C3=C(N)N=C(N)N=C3C=C2)=CC(OC)=C1OC

InChI

InChIKey=NOYPYLRCIDNJJB-UHFFFAOYSA-N

InChI=1S/C19H23N5O3/c1-10-11(5-6-13-16(10)18(20)24-19(21)23-13)9-22-12-7-14(25-2)17(27-4)15(8-12)26-3/h5-8,22H,9H2,1-4H3,(H4,20,21,23,24)

HIDE SMILES / InChI

Description
Sources: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ad0f8925-f817-4460-aa6b-172a043a440b | https://www.ncbi.nlm.nih.gov/pubmed/15361639 | https://www.ncbi.nlm.nih.gov/pubmed/16199980

Trimetrexate, a second-generation folate antagonist which was used under brand name NEUTREXIN with concurrent leucovorin administration (leucovorin protection) was indicated as an alternative therapy for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with the acquired immunodeficiency syndrome (AIDS). Nevertheless, this product was discontinued. In present time, trimetrexate with a different combinations is in the phase II of clinical trial for the treatment the following cancer diseases: pancreatic cancer and colorectal cancer (in combination with fluorouracil and leucovorin) and to treat a refractory acute leukemia in combination with leucovorin. Trimetrexate is a competitive inhibitor of dihydrofolate reductase (DHFR) from bacterial, protozoan, and mammalian sources. DHFR catalyzes the reduction of intracellular dihydrofolate to the active coenzyme tetrahydrofolate. Inhibition of DHFR results in the depletion of this coenzyme, leading directly to interference with thymidylate biosynthesis, as well as inhibition of folate-dependent formyltransferases, and indirectly to inhibition of purine biosynthesis. The result is disruption of DNA, RNA, and protein synthesis, with consequent cell death.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Dihydrofolate reductase 57 Target ID: CHEMBL1926 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11448221	Inhibitor 8297
Dihydrofolate reductase 57 Target ID: P00374 Gene ID: 1719.0 Gene Symbol: DHFR Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/12649191	Inhibitor 8297

Conditions

Condition	Modality	Highest Phase	Product
Pneumocystis carinii pneumonia 4 Sources: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ad0f8925-f817-4460-aa6b-172a043a440b	Curative	Approved 8429	NEUTREXIN Approved Use Neutrexin (trimetrexate glucuronate for injection) with concurrent leucovorin administration (leucovorin protection) is indicated as an alternative therapy for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with the acquired immunodeficiency syndrome (AIDS), who are intolerant of, or are refractory to, trimethoprim-sulfamethoxazole therapy or for whom trimethoprim-sulfamethoxazole is contraindicated. This indication is based on the results of a randomized, controlled double-blind trial comparing Neutrexin with concurrent leucovorin protection (TMTX/LV) to trimethoprim sulfamethoxazole (TMP/SMX) in patients with moderate-to-severe Pneumocystis carinii pneumonia, as well as results of a Treatment IND. Launch Date 7.5608641E11
Pancreatic cancer 97 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15361639	Primary	Phase II 1132	Unknown Approved Use Unknown
Colorectal cancer 101 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16199980	Primary	Phase II 1132	Unknown Approved Use Unknown
Refractory acute leukemia 4 Sources: https://www.ncbi.nlm.nih.gov/pubmed/7834472	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
3.1 mg/L REVIEW https://www.ncbi.nlm.nih.gov/pubmed/7789290	30 mg/m² 1 times / day steady-state, intravenous dose: 30 mg/m² route of administration: Intravenous experiment type: STEADY-STATE co-administered: LEUCOVORIN CALCIUM	LEUCOVORIN CALCIUM	TRIMETREXATE plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
15.8 mg × h/L REVIEW https://www.ncbi.nlm.nih.gov/pubmed/7789290	30 mg/m² 1 times / day steady-state, intravenous dose: 30 mg/m² route of administration: Intravenous experiment type: STEADY-STATE co-administered: LEUCOVORIN CALCIUM	LEUCOVORIN CALCIUM	TRIMETREXATE plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
11 h REVIEW https://www.ncbi.nlm.nih.gov/pubmed/7789290	30 mg/m² 1 times / day steady-state, intravenous dose: 30 mg/m² route of administration: Intravenous experiment type: STEADY-STATE co-administered: LEUCOVORIN CALCIUM	LEUCOVORIN CALCIUM	TRIMETREXATE plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
100 mg/m2 1 times / week multiple, intravenous MTD Dose: 100 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 100 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/	unhealthy, 49 years n = 1 Health Status: unhealthy Condition: pulmonary and pleural metastasis from cutaneous angiosarcoma Age Group: 49 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/	Disc. AE: Death... AEs leading to discontinuation/dose reduction: Death (grade 5) Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/
75 mg/m2 single, intravenous MTD Dose: 75 mg/m2 Route: intravenous Route: single Dose: 75 mg/m2 Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/	unhealthy, 63 years n = 1 Health Status: unhealthy Condition: adenocarcinoma of the lung Age Group: 63 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/	Disc. AE: Death... AEs leading to discontinuation/dose reduction: Death (grade 5) Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/
10 mg/m2 1 times / day steady, intravenous MTD Dose: 10 mg/m2, 1 times / day Route: intravenous Route: steady Dose: 10 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/1831340/	unhealthy, adult n = 17 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 17 Sources: https://pubmed.ncbi.nlm.nih.gov/1831340/	Other AEs: Gastrointestinal signs and symptoms... Other AEs: Gastrointestinal signs and symptoms Sources: https://pubmed.ncbi.nlm.nih.gov/1831340/
100 mg/m2 1 times / week multiple, intravenous MTD Dose: 100 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 100 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/	unhealthy, adult n = 4 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/	DLT: Myelosuppression... Other AEs: Hematotoxicity... Dose limiting toxicities: Myelosuppression Other AEs: Hematotoxicity (grade 3, 2 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/
110 mg/m2 1 times / week multiple, intravenous MTD Dose: 110 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 110 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/	unhealthy, adult n = 3 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/	DLT: Myelosuppression... Dose limiting toxicities: Myelosuppression Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/
130 mg/m2 1 times / week multiple, intravenous MTD Dose: 130 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 130 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/	unhealthy, adult n = 7 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/	DLT: Myelosuppression... Disc. AE: Hematotoxicity... Dose limiting toxicities: Myelosuppression AEs leading to discontinuation/dose reduction: Hematotoxicity (grade 2, 2 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/
15 mg/m2 single, intravenous MTD Dose: 15 mg/m2 Route: intravenous Route: single Dose: 15 mg/m2 Sources: https://pubmed.ncbi.nlm.nih.gov/1831340/	unhealthy, adult n = 18 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 18 Sources: https://pubmed.ncbi.nlm.nih.gov/1831340/	Other AEs: Gastrointestinal signs and symptoms... Other AEs: Gastrointestinal signs and symptoms Sources: https://pubmed.ncbi.nlm.nih.gov/1831340/
155 mg/m2 1 times / week multiple, intravenous (max) MTD Dose: 155 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 155 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/	unhealthy, adult n = 29 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 29 Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/	Disc. AE: Hematotoxicity... AEs leading to discontinuation/dose reduction: Hematotoxicity (grade 2, 12 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/
155 mg/m2 1 times / week multiple, intravenous MTD Dose: 155 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 155 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/	unhealthy, adult n = 2 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/	DLT: Myelosuppression... Dose limiting toxicities: Myelosuppression Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/
50 mg/m2 1 times / week multiple, intravenous MTD Dose: 50 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 50 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/	unhealthy, adult n = 7 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/	DLT: Myelosuppression... Dose limiting toxicities: Myelosuppression Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/
75 mg/m2 1 times / week multiple, intravenous MTD Dose: 75 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 75 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/	unhealthy, adult n = 8 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/	DLT: Myelosuppression... Dose limiting toxicities: Myelosuppression Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/
90 mg/m2 1 times / week multiple, intravenous MTD Dose: 90 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 90 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/	unhealthy, adult n = 6 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/	DLT: Myelosuppression... Disc. AE: Hematotoxicity... Dose limiting toxicities: Myelosuppression AEs leading to discontinuation/dose reduction: Hematotoxicity (grade 2, 1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/2953412/

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP 450 31

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP 450 31	substrate 3367 Sources: https://link.springer.com/article/10.2165/00003495-199549040-00007; https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020083s048s049s050lbl.pdf#page=18	yes		likely (co-administration study) Comment: concomitant administration of SPORANOX (itraconazole) and trimetrexate may inhibit the metabolism of trimetrexate Sources: https://link.springer.com/article/10.2165/00003495-199549040-00007; https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020083s048s049s050lbl.pdf#page=18

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY558210	https://www.001chemical.com/chem/52128-35-5
AA Blocks	AA00DB6L	https://www.aablocks.com/goods/Goods/detail?id=AA00DB6L
Achemtek	0101-002318	http://www.achemtek.com/52128-35-5
Adooq BioScience	A12796	https://www.adooq.com/trimetrexate.html
Ambinter	Amb22731961	http://www.ambinter.com/reference/22731961
Angel Pharmatech	AG302845	http://www.angelpharmatech.com/52128-35-5.html
BLD Pharm	BD155583	http://www.bldpharm.com/products/52128-35-5.html
BioChemPartner	BCP15515	http://www.biochempartner.com/52128-35-5-BCP15515
CSNpharm	CSN12149	https://www.csnpharm.com/products/trimetrexate.html
Chem Scene	CS-4063	http://www.chemscene.com/52128-35-5.html
Chemspace	CSSB00020617805	https://chem-space.com/CSSB00020617805
DC Chemicals	DC23932	http://www.dcchemicals.com/product_show-DC23932.html
Finetech	FT-0649497	http://www.finetechnology-ind.com/prod/detail/pub/52128-35-5.html
Lab Network	LN01342098	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01342098
MedChem Express	HY-10373	https://www.medchemexpress.com/Trimetrexate.html
Molcore	MC558210	https://www.molcore.com/product/52128-35-5
Parchem	30218	http://www.parchem.com/chemical-supplier-distributor/Trimetrexate-020218.aspx
Smolecule	S545904	http://www.smolecule.com/products/s545904
Smolecule	S772620	https://www.smolecule.com/products/s772620
THE BioTek	bt-287020	https://www.thebiotek.com/product/inhibitors/bt-287020
eNovation Chemicals	D673579	https://www.enovationchem.com/ProductDetails.asp?ProductID=D673579

PubMed

Title	Date	PubMed
Treatment of experimental pneumocystosis: review of 7 years of experience and development of a new system for classifying antimicrobial drugs.	1992 Sep	1416885
Expression and characterization of recombinant human-derived Pneumocystis carinii dihydrofolate reductase.	2000 Nov	11036028
Marked suppression of the activity of some, but not all, antifolate compounds by augmentation of folate cofactor pools within tumor cells.	2001 Apr 1	11274972
RD114-pseudotyped oncoretroviral vectors. Biological and physical properties.	2001 Jun	11458516
A meta-analysis of salvage therapy for Pneumocystis carinii pneumonia.	2001 Jun 25	11427101
Synthesis of 2,4-diamino-6-(thioarylmethyl)pyrido[2,3-d]pyrimidines as dihydrofolate reductase inhibitors.	2001 Nov	11597474
Methylthioadenosine phosphorylase as target for chemoselective treatment of T-cell acute lymphoblastic leukemic cells.	2002 Jan-Feb	11987241
Resistance to multiple novel antifolates is mediated via defective drug transport resulting from clustered mutations in the reduced folate carrier gene in human leukaemia cell lines.	2002 Nov 1	12139489
Analysis of quinazoline and pyrido[2,3-d]pyrimidine N9-C10 reversed-bridge antifolates in complex with NADP+ and Pneumocystis carinii dihydrofolate reductase.	2002 Sep	12198294
Quinoxaline chemistry. Part 15. 4-[2-Quinoxalylmethylenimino]-benzoylglutamates and -benzoates, 4-[2-quinoxalylmethyl-N-methylamino]-benzoylglutamates as analogues of classical antifolate agents. Synthesis, elucidation of structures and in vitro evaluation of antifolate and anticancer activities.	2003 Jan	12595037
Chemotherapy for malignant pleural mesothelioma: past results and recent developments.	2003 Jan 27	12610498
Sulfa resistance and dihydropteroate synthase mutants in recurrent Pneumocystis carinii pneumonia.	2003 Jul	12890330
A new nonlinear mixture response surface paradigm for the study of synergism: a three drug example.	2003 Oct	14529372
Design, synthesis, and biological evaluation of 2,4-diamino-5-methyl-6-substituted-pyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors.	2004 Jul 1	15214795
Dihydropteroate synthase gene mutations in Pneumocystis and sulfa resistance.	2004 Oct	15504256
Prediction of genotoxicity of chemical compounds by statistical learning methods.	2005 Jun	15962942
Mutant Gly482 and Thr482 ABCG2 mediate high-level resistance to lipophilic antifolates.	2006 Dec	16612649
Quantitative correlation between promoter methylation and messenger RNA levels of the reduced folate carrier.	2008 May 1	18452618
Clinical efficacy of first- and second-line treatments for HIV-associated Pneumocystis jirovecii pneumonia: a tri-centre cohort study.	2009 Dec	19858161
Structures of dihydrofolate reductase-thymidylate synthase of Trypanosoma cruzi in the folate-free state and in complex with two antifolate drugs, trimetrexate and methotrexate.	2009 Jul	19564691
The immunobiology of cord blood transplantation.	2010 Dec	21253423
Gateways to clinical trials.	2010 Dec	21225012
Application and review of the separate ray model to investigate interaction effects.	2010 Jan 1	20036877
Comparison of methods for statistical analysis of combination studies.	2010 Jan 1	20036875
Cancer chemotherapy: targeting folic acid synthesis.	2010 Nov 19	21301589

Patents

Sample Use Guides

In Vivo Use Guide

Neutrexin (trimetrexate glucuronate for injection) is administered at a dose of 45 mg/m2 once daily by intravenous infusion over 60 minutes. Leucovorin must be administered daily during treatment with Neutrexin and for 72 hours past the last dose of Neutrexin. Leucovorin may be administered intravenously at a dose of 20 mg/m2 over 5 to 10 minutes every 6 hours for a total daily dose of 80 mg/m2, or orally as 4 doses of 20 mg/m2 spaced equally throughout the day. The oral dose should be rounded up to the next higher 25 mg increment. The recommended course of therapy is 21 days of Neutrexin and 24 days of leucovorin.

Route of Administration: Intravenous

In Vitro Use Guide

Carboxypeptidase G2 (CPG2), an enzyme produced by Pseudomonas strain RS-16, hydrolyzes the glutamate residue from methotrexate and other folates. The possibility of enhancing trimetrexate cytotoxicity by CPG2 induced folate depletion was investigated in vitro in a human leukemia cell line, CCRF-CEM, and in three sublines of these cells each with a different methotrexate resistance phenotype. Trimetrexate alone was cytotoxic against the parent and all the resistant cell lines with the drug concentrations required to decrease the cell count to 50% of control in the nanomolar range (1.4, 1.6, 1.5, and 0.7 nM in CCRF-CEM, CCRF-CEM/E, CCRF-CEM/P, and CCRF-CEM/T, respectively) following 5 days of exposure.

Name

Type

Language

TRIMETREXATE

Official Name

English

Trimetrexate [WHO-DD]

Common Name

English

TRIMETREXATE [USAN]

Common Name

English

2,4-Diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline

Systematic Name

English

2,4-QUINAZOLINEDIAMINE, 5-METHYL-6-(((3,4,5-TRIMETHOXYPHENYL)AMINO)METHYL)-

Systematic Name

English

TRIMETREXATE [HSDB]

Common Name

English

TRIMETREXATE [VANDF]

Common Name

English

NSC-249008

Code

English

TRIMETREXATE [MI]

Common Name

English

trimetrexate [INN]

Common Name

English

Classification Tree Code System Code

WHO-ATC

P01AX07