PEMETREXED

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C20H21N5O6
Molecular Weight	427.4106
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

NC1=NC2=C(C(CCC3=CC=C(C=C3)C(=O)N[C@@H](CCC(O)=O)C(O)=O)=CN2)C(=O)N1

InChI

InChIKey=WBXPDJSOTKVWSJ-ZDUSSCGKSA-N

InChI=1S/C20H21N5O6/c21-20-24-16-15(18(29)25-20)12(9-22-16)6-3-10-1-4-11(5-2-10)17(28)23-13(19(30)31)7-8-14(26)27/h1-2,4-5,9,13H,3,6-8H2,(H,23,28)(H,26,27)(H,30,31)(H4,21,22,24,25,29)/t13-/m0/s1

HIDE SMILES / InChI

Molecular Formula	C20H21N5O6
Molecular Weight	427.4106
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021462s021lbl.pdf
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/9762351 https://www.ncbi.nlm.nih.gov/pubmed/17308042

Pemetrexed is a new-generation antifolate, approved for the treatment of mesothelioma and non-small cell lung cancer, currently being evaluated for the treatment of a variety of other solid tumors. Pemetrexed, is a folate analog metabolic inhibitor that exerts its action by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltransferase (GARFT) and and to a lesser extent aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such as the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, is thought to occur to a lesser extent, in normal tissues. Polyglutamated metabolites are thought to have an increased intracellular half-life resulting in prolonged drug action in malignant cells.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Thymidylate synthase 32 Target ID: CHEMBL1952 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9762351	Inhibitor 8297	109.0 nM [Ki]
Dihydrofolate reductase 57 Target ID: CHEMBL202 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9762351	Inhibitor 8297	7.0 nM [Ki]
GAR transformylase 11 Target ID: CHEMBL3972 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9762351	Inhibitor 8297	9300.0 nM [Ki]
AICAR transformylase 9 Target ID: CHEMBL2518 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9762351	Inhibitor 8297	3580.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Nonsquamous non-small cell lung cancer 9 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021462s021lbl.pdf	Primary		Approved 8429	ALIMTA Approved Use ALIMTA® is a folate analog metabolic inhibitor indicated for: Locally Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer: Initial treatment in combination with cisplatin. (1.1) Maintenance treatment of patients whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. (1.2) After prior chemotherapy as a single-agent. (1.3) Mesothelioma: in combination with cisplatin. (1.4) Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. (1.5) 1.1 Nonsquamous Non-Small Cell Lung Cancer – Combination with Cisplatin ALIMTA® is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. 1.2 Nonsquamous Non-Small Cell Lung Cancer – Maintenance ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. 1.3 Nonsquamous Non-Small Cell Lung Cancer – After Prior Chemotherapy ALIMTA is indicated as a single-agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy. 1.4 Mesothelioma ALIMTA in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. 1.5 Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. [see Clinical Studies (14.1, 14.2, 14.3) Launch Date 2004
Malignant pleural mesothelioma 11 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021462s021lbl.pdf	Primary		Approved 8429	ALIMTA Approved Use ALIMTA® is a folate analog metabolic inhibitor indicated for: Locally Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer: Initial treatment in combination with cisplatin. (1.1) Maintenance treatment of patients whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. (1.2) After prior chemotherapy as a single-agent. (1.3) Mesothelioma: in combination with cisplatin. (1.4) Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. (1.5) 1.1 Nonsquamous Non-Small Cell Lung Cancer – Combination with Cisplatin ALIMTA® is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. 1.2 Nonsquamous Non-Small Cell Lung Cancer – Maintenance ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. 1.3 Nonsquamous Non-Small Cell Lung Cancer – After Prior Chemotherapy ALIMTA is indicated as a single-agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy. 1.4 Mesothelioma ALIMTA in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. 1.5 Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. [see Clinical Studies (14.1, 14.2, 14.3) Launch Date 2004

C_max

Value	Dose	Co-administered	Analyte	Population
137 μg/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/16391300	500 mg/m² other, intravenous dose: 500 mg/m² route of administration: Intravenous experiment type: OTHER co-administered:		PEMETREXED blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
164 μg × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/16391300	500 mg/m² other, intravenous dose: 500 mg/m² route of administration: Intravenous experiment type: OTHER co-administered:		PEMETREXED blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
3.71 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/16391300	500 mg/m² other, intravenous dose: 500 mg/m² route of administration: Intravenous experiment type: OTHER co-administered:		PEMETREXED blood	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
19% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021462s021lbl.pdf			PEMETREXED plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
1200 mg/m2 1 times / 2 weeks multiple, intravenous Highest studied dose Dose: 1200 mg/m2, 1 times / 2 weeks Route: intravenous Route: multiple Dose: 1200 mg/m2, 1 times / 2 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/32520407	unhealthy, 63.7 years (range: 47–77 years) n = 7 Health Status: unhealthy Condition: Recurrent or Progressive Central Nervous System Lymphoma Age Group: 63.7 years (range: 47–77 years) Sex: M+F Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/32520407	DLT: Lymphopenia... Other AEs: Neutropenia, Fatigue... Dose limiting toxicities: Lymphopenia (grade 4, 2 patients) Other AEs: Neutropenia (grade 3-4) Fatigue (grade 3-4) Sources: https://pubmed.ncbi.nlm.nih.gov/32520407
900 mg/m2 1 times / 2 weeks multiple, intravenous MTD Dose: 900 mg/m2, 1 times / 2 weeks Route: intravenous Route: multiple Dose: 900 mg/m2, 1 times / 2 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/32520407	unhealthy, 63.7 years (range: 47–77 years) n = 4 Health Status: unhealthy Condition: Recurrent or Progressive Central Nervous System Lymphoma Age Group: 63.7 years (range: 47–77 years) Sex: M+F Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/32520407	Disc. AE: Transaminases increased... AEs leading to discontinuation/dose reduction: Transaminases increased (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/32520407
600 mg/m2 1 times / 2 weeks multiple, intravenous Dose: 600 mg/m2, 1 times / 2 weeks Route: intravenous Route: multiple Dose: 600 mg/m2, 1 times / 2 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/32520407	unhealthy, 63.7 years (range: 47–77 years) n = 6 Health Status: unhealthy Condition: Recurrent or Progressive Central Nervous System Lymphoma Age Group: 63.7 years (range: 47–77 years) Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/32520407	DLT: Neutropenia... Dose limiting toxicities: Neutropenia (grade 4, 1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/32520407

AEs

AE	Significance	Dose	Population
Fatigue	grade 3-4	1200 mg/m2 1 times / 2 weeks multiple, intravenous Highest studied dose Dose: 1200 mg/m2, 1 times / 2 weeks Route: intravenous Route: multiple Dose: 1200 mg/m2, 1 times / 2 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/32520407	unhealthy, 63.7 years (range: 47–77 years) n = 7 Health Status: unhealthy Condition: Recurrent or Progressive Central Nervous System Lymphoma Age Group: 63.7 years (range: 47–77 years) Sex: M+F Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/32520407
Neutropenia	grade 3-4	1200 mg/m2 1 times / 2 weeks multiple, intravenous Highest studied dose Dose: 1200 mg/m2, 1 times / 2 weeks Route: intravenous Route: multiple Dose: 1200 mg/m2, 1 times / 2 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/32520407	unhealthy, 63.7 years (range: 47–77 years) n = 7 Health Status: unhealthy Condition: Recurrent or Progressive Central Nervous System Lymphoma Age Group: 63.7 years (range: 47–77 years) Sex: M+F Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/32520407
Lymphopenia	grade 4, 2 patients DLT	1200 mg/m2 1 times / 2 weeks multiple, intravenous Highest studied dose Dose: 1200 mg/m2, 1 times / 2 weeks Route: intravenous Route: multiple Dose: 1200 mg/m2, 1 times / 2 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/32520407	unhealthy, 63.7 years (range: 47–77 years) n = 7 Health Status: unhealthy Condition: Recurrent or Progressive Central Nervous System Lymphoma Age Group: 63.7 years (range: 47–77 years) Sex: M+F Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/32520407
Transaminases increased	1 patient Disc. AE	900 mg/m2 1 times / 2 weeks multiple, intravenous MTD Dose: 900 mg/m2, 1 times / 2 weeks Route: intravenous Route: multiple Dose: 900 mg/m2, 1 times / 2 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/32520407	unhealthy, 63.7 years (range: 47–77 years) n = 4 Health Status: unhealthy Condition: Recurrent or Progressive Central Nervous System Lymphoma Age Group: 63.7 years (range: 47–77 years) Sex: M+F Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/32520407
Neutropenia	grade 4, 1 patient DLT, Disc. AE	600 mg/m2 1 times / 2 weeks multiple, intravenous Dose: 600 mg/m2, 1 times / 2 weeks Route: intravenous Route: multiple Dose: 600 mg/m2, 1 times / 2 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/32520407	unhealthy, 63.7 years (range: 47–77 years) n = 6 Health Status: unhealthy Condition: Recurrent or Progressive Central Nervous System Lymphoma Age Group: 63.7 years (range: 47–77 years) Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/32520407

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 MRP5 22	OAT3 339 OAT4 78 MRP5 40

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-462.pdf_Alimta_BioPharmr_P1.pdf#page=16 Page: 16.0	not significant
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-462.pdf_Alimta_BioPharmr_P1.pdf#page=16 Page: 16.0	not significant
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-462.pdf_Alimta_BioPharmr_P1.pdf#page=16 Page: 16.0	not significant
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-462.pdf_Alimta_BioPharmr_P1.pdf#page=16 Page: 16.0	not significant
MRP5 48	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/16337112/	yes [Ki 300 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
MRP5 40	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/16337112/	yes
OAT4 78	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209472s000lbl.pdf#page=17 Page: 17.0	yes
OAT3 339	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209472s000lbl.pdf#page=17 Page: 17.0	yes	weak (co-administration study) Comment: coadministration with ibuprofen decreased the clearance of pemetrexed and increased its expsoure (AUC) by ~ 20% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209472s000lbl.pdf#page=17 Page: 17.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/021462s015.pdf#page=73 Page: 73.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:63616	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:63616
ChemicalBook	CB4170583	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB4170583
MolPort	MolPort-016-638-470	https://www.molport.com/shop/molecule-link/MolPort-016-638-470
MolPort	MolPort-020-179-988	https://www.molport.com/shop/molecule-link/MolPort-020-179-988
ZINC	ZINC000001540998	http://zinc15.docking.org/substances/ZINC000001540998
eMolecules	30513153	https://www.emolecules.com/cgi-bin/more?vid=30513153
eMolecules	37036813	https://www.emolecules.com/cgi-bin/more?vid=37036813

PubMed

Title	Date	PubMed
Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors.	2001	11524555
A new route to 7-substituted derivatives of n-[4-(2-[2-amino-3,4-dihydro-4-oxo-7H-pyrrolo(2,3-d)pyrimidin-5-yl]ethyl)benzoyl]-L-glutamic acid [ALIMTA (LY231514, MTA)].	2001 Jun 1	11374991
Pemetrexed (Alimta): a novel multitargeted antifolate agent.	2003 Apr	12722874
Design, synthesis, and biological activities of classical N-[4-[2-(2-amino-4-ethylpyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid and its 6-methyl derivative as potential dual inhibitors of thymidylate synthase and dihydrofolate reductase and as potential antitumor agents.	2003 Feb 13	12570380
Accumulation of 5-phosphoribosyl-1-pyrophosphate in human CCRF-CEM leukaemia cells treated with antifolates.	2004 Mar	14687931
Biochemical pharmacology of pemetrexed.	2004 Nov	15655931
Pemetrexed: a multitargeted antifolate.	2005 Sep	16291410
Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications.	2007 Feb	17308042
Pemetrexed: a review of its use in the management of advanced non-squamous non-small cell lung cancer.	2009 Nov 12	19852529

Patents

Sample Use Guides

In Vivo Use Guide

Combination ALIMTA (pemetrexed disodium) use in Non-Small Cell Lung Cancer and Mesothelioma: Recommended dose of ALIMTA is 500 mg/m2 i.v. on Day 1 of each 21-day cycle in combination with cisplatin 75 mg/m2 i.v. beginning 30 minutes after ALIMTA administration. Single-Agent use in Non-Small Cell Lung Cancer: Recommended dose of ALIMTA is 500 mg/m2 i.v. on Day 1 of each 21-day cycle. Dose Reductions: Dose reductions or discontinuation may be needed based on toxicities from the preceding cycle of therapy.

Route of Administration: Intravenous

In Vitro Use Guide

pemetrexed has a potent cytotoxic effect against human peripheral blood lymphocytes at concentrations 25, 50, 75 and 100 μg/mL (concentrations roughly 2,25–9 times less than the maximum plasma level (225 μg/mL) achieved in patients receiving this drug) based on the top concentration (100 μg/mL)

Substance Class	Chemical Created by `admin` on `Fri Dec 15 15:47:00 GMT 2023` Edited by `admin` on `Fri Dec 15 15:47:00 GMT 2023`
Record UNII	04Q9AIZ7NO
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

PEMETREXED

Official Name

English

pemetrexed [INN]

Common Name

English

PEMFEXY

Brand Name

English

N-(P-(2-(2-AMINO-4,7-DIHYDRO-4-OXO-1H-PYRROLO(2,3-D)PYRIMIDIN-5-YL)ETHYL)BENZOYL)-L-GLUTAMATE

Systematic Name

English

PEMETREXED [HSDB]

Common Name

English

L-GLUTAMIC ACID, N-(4-(2-(2-AMINO-4,7-DIHYDRO-4-OXO-3H-PYRROLO(2,3-D)PYRIMIDIN-5-YL)ETHYL)BENZOYL)-

Systematic Name

English

N-(4-(2-(2-AMINO-4,7-DIHYDRO-4-OXO-1H-PYRROLO(2,3-D)PYRIMIDIN-5-YL)ETHYL)BENZOYL)-L-GLUTAMIC ACID

Systematic Name

English

LY-231514

Code

English

PEMETREXED [EMA EPAR]

Common Name

English

LY231514

Code

English

PEMETREXED [ORANGE BOOK]

Common Name

English

Pemetrexed [WHO-DD]

Common Name

English

PEMETREXED [MI]

Common Name

English

PEMETREXED [VANDF]

Common Name

English

NSC-698037

Code

English

Classification Tree Code System Code

EMA ASSESSMENT REPORTS

PEMETREXED LILLY (AUTHORIZED: CARCINOMA, NON-SMALL-CELL LUNG, MESOTHELIOMA)