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Details

Stereochemistry ABSOLUTE
Molecular Formula C20H21N5O6.2C6H14N4O2
Molecular Weight 775.8126
Optical Activity UNSPECIFIED
Defined Stereocenters 3 / 3
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of PEMETREXED DIARGININE

SMILES

N[C@@H](CCCNC(N)=N)C(O)=O.N[C@@H](CCCNC(N)=N)C(O)=O.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=PDRNJKDODQMLSW-HZVMSULOSA-N
InChI=1S/C20H21N5O6.2C6H14N4O2/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;2*7-4(5(11)12)2-1-3-10-6(8)9/h1-2,4-5,9,13H,3,6-8H2,(H,23,28)(H,26,27)(H,30,31)(H4,21,22,24,25,29);2*4H,1-3,7H2,(H,11,12)(H4,8,9,10)/t13-;2*4-/m000/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

Molecular Formula C6H14N4O2
Molecular Weight 174.201
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Description
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

Curator's Comment: Known to be CNS penetrant in rodents https://www.ncbi.nlm.nih.gov/pubmed/15987831 https://www.ncbi.nlm.nih.gov/pubmed/23297298 Human data not available, but is known that pemetrexed-based treatments controls of brain metastases in the treatment of non-small-cell lung cancer https://www.ncbi.nlm.nih.gov/pubmed/21831719

Originator

Curator's Comment: # Eli Lilly

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
109.0 nM [Ki]
7.0 nM [Ki]
9300.0 nM [Ki]
3580.0 nM [Ki]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
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

1.09287362E12
Primary
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

1.09287362E12
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
137 μg/mL
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

AUC

ValueDoseCo-administeredAnalytePopulation
164 μg × h/mL
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
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
3.71 h
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
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
19%
PEMETREXED plasma
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse 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:
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:
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:
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:
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:
Disc. AE: Transaminases increased...
AEs leading to
discontinuation/dose reduction:
Transaminases increased (1 patient)
Sources:
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:
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:
DLT: Neutropenia...
Dose limiting toxicities:
Neutropenia (grade 4, 1 patient)
Sources:
AEs

AEs

AESignificanceDosePopulation
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:
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:
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:
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:
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:
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:
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:
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:
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:
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:
Overview

Overview

OverviewOther

Other InhibitorOther SubstrateOther Inducer





Drug as perpetrator​Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
yes
yes
yes
weak (co-administration study)
Comment: coadministration with ibuprofen decreased the clearance of pemetrexed and increased its expsoure (AUC) by ~ 20%
Page: 17.0
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors.
2001
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
Pemetrexed (Alimta): a novel multitargeted antifolate agent.
2003 Apr
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
Accumulation of 5-phosphoribosyl-1-pyrophosphate in human CCRF-CEM leukaemia cells treated with antifolates.
2004 Mar
Pemetrexed: a review of its use in the management of advanced non-squamous non-small cell lung cancer.
2009 Nov 12
Patents

Sample Use Guides

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
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 Thu Jul 06 16:15:45 UTC 2023
Edited
by admin
on Thu Jul 06 16:15:45 UTC 2023
Record UNII
3NGW6TX8EK
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
PEMETREXED DIARGININE
Common Name English
Pemetrexed diarginine [WHO-DD]
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)-, COMPD. WITH L-ARGININE (1:2)
Systematic Name English
ZENTIVA
Brand Name English
Code System Code Type Description
FDA UNII
3NGW6TX8EK
Created by admin on Thu Jul 06 16:15:45 UTC 2023 , Edited by admin on Thu Jul 06 16:15:45 UTC 2023
PRIMARY
SMS_ID
300000032800
Created by admin on Thu Jul 06 16:15:45 UTC 2023 , Edited by admin on Thu Jul 06 16:15:45 UTC 2023
PRIMARY
CAS
1639418-21-5
Created by admin on Thu Jul 06 16:15:45 UTC 2023 , Edited by admin on Thu Jul 06 16:15:45 UTC 2023
PRIMARY
PUBCHEM
145996797
Created by admin on Thu Jul 06 16:15:45 UTC 2023 , Edited by admin on Thu Jul 06 16:15:45 UTC 2023
PRIMARY
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PARENT -> SALT/SOLVATE
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ACTIVE MOIETY