Identification

Name
Trimetazidine
Accession Number
DB09069
Type
Small Molecule
Groups
Approved, Investigational
Description

Trimetazidine is a drug for angina pectoris sold under the brand name Vastarel MR. Trimetazidine is described as the first cytoprotective anti-ischemic agent developed and marketed by Laboratoires Servier (France). Trimetazidine is an anti-ischemic (anti-anginal) metabolic agent, which improves myocardial glucose utilization through inhibition of long-chain 3-ketoacyl CoA thiolase activity, which results in a reduction in fatty acid oxidation and a stimulation of glucose oxidation. High fatty acid oxidation rates are detrimental during ischemia due to an inhibition of glucose oxidation leading to uncoupling of glycolysis and an increase in proton production, which has the potential to accelerate sodium and calcium overload in the heart, which leads to an exacerbation of ischemic injury and decreased cardiac efficiency during reperfusion.

Structure
Thumb
Synonyms
  • 1-[2,3,4-trimethoxybenzyl] piperazine dihydrochloride
  • Trimetazidina
External IDs
40045
Product Ingredients
IngredientUNIICASInChI Key
Trimetazidine dihydrochloride48V6723Z1P13171-25-0VYFLPFGUVGMBEP-UHFFFAOYSA-N
International/Other Brands
Vastarel MR (Laboratoires Servier)
Categories
UNII
N9A0A0R9S8
CAS number
5011-34-7
Weight
Average: 266.341
Monoisotopic: 266.163042576
Chemical Formula
C14H22N2O3
InChI Key
UHWVSEOVJBQKBE-UHFFFAOYSA-N
InChI
InChI=1S/C14H22N2O3/c1-17-12-5-4-11(13(18-2)14(12)19-3)10-16-8-6-15-7-9-16/h4-5,15H,6-10H2,1-3H3
IUPAC Name
1-[(2,3,4-trimethoxyphenyl)methyl]piperazine
SMILES
COC1=C(OC)C(OC)=C(CN2CCNCC2)C=C1

Pharmacology

Indication

Trimetazidine is indicated for use in angina pectoris.

Pharmacodynamics
Not Available
Mechanism of action

Trimetazidine is an anti-ischemic (anti-anginal) metabolic agent, which improves myocardial glucose utilization through inhibition of long-chain 3-ketoacyl CoA thiolase activity, which results in a reduction in fatty acid oxidation and a stimulation of glucose oxidation. High fatty acid oxidation rates are detrimental during ischemia due to an inhibition of glucose oxidation leading to uncoupling of glycolysis and an increase in proton production, which has the potential to accelerate sodium and calcium overload in the heart. This leads to an exacerbation of ischemic injury and decreased cardiac efficiency during reperfusion.

TargetActionsOrganism
A3-ketoacyl-CoA thiolase, peroxisomal
inhibitor
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

Half life of the modified release (MR) formulation was reported to be ∼8 h in young volunteers (25 ± 8) and ∼12 h in elderly (72 ± 4) (Barré et al. 2003).

Clearance
Not Available
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
MetoclopramideThe risk or severity of adverse effects can be increased when Metoclopramide is combined with Trimetazidine.
Patent BlueThe therapeutic efficacy of Trimetazidine can be decreased when used in combination with Patent Blue.
Food Interactions
Not Available

References

General References
  1. Kantor PF, Lucien A, Kozak R, Lopaschuk GD: The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res. 2000 Mar 17;86(5):580-8. [PubMed:10720420]
  2. Onay-Besikci A, Ozkan SA: Trimetazidine revisited: a comprehensive review of the pharmacological effects and analytical techniques for the determination of trimetazidine. Cardiovasc Ther. 2008 Summer;26(2):147-65. doi: 10.1111/j.1527-3466.2008.00043.x. [PubMed:18485136]
  3. Reymond F, Steyaert G, Carrupt PA, Morin D, Tillement JP, Girault HH, Testa B: The pH-partition profile of the anti-ischemic drug trimetazidine may explain its reduction of intracellular acidosis. Pharm Res. 1999 May;16(5):616-24. [PubMed:10350001]
  4. McClellan KJ, Plosker GL: Trimetazidine. A review of its use in stable angina pectoris and other coronary conditions. Drugs. 1999 Jul;58(1):143-57. [PubMed:10439934]
  5. Barre J, Ledudal P, Oosterhuis B, Brakenhoff JP, Wilkens G, Sollie FA, Tran D: Pharmacokinetic profile of a modified release formulation of trimetazidine (TMZ MR 35 mg) in the elderly and patients with renal failure. Biopharm Drug Dispos. 2003 May;24(4):159-64. [PubMed:12698499]
External Links
KEGG Drug
D01606
PubChem Compound
21109
PubChem Substance
310265002
ChemSpider
19853
BindingDB
80613
ChEBI
94789
ChEMBL
CHEMBL203266
Drugs.com
Drugs.com Drug Page
Wikipedia
Trimetazidine
ATC Codes
C01EB15 — Trimetazidine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Not Yet RecruitingOtherAcute-On-Chronic Liver Failure1
2Active Not RecruitingBasic ScienceInhibition of Platelet Aggregation in Response to Clopidogrel May be Accentuated by Trimetazidine / Platelet Dysfunction Due to Drugs1
2RecruitingTreatmentPulmonary Arterial Hypertension (PAH)1
2Unknown StatusTreatmentHypertrophic Cardiomyopathy1
3RecruitingPreventionDiabetes Mellitus (DM) / Unstable Angina (UA)1
3RecruitingTreatmentHCC2
4CompletedTreatmentCoronary Artery Disease / Type 2 Diabetes Mellitus1
4Not Yet RecruitingTreatmentCoronary Artery Disease2
4RecruitingTreatmentCoronary Artery Disease / Microcirculation / Vascular Resistance1
Not AvailableEnrolling by InvitationTreatmentCardiovascular Disease (CVD)1
Not AvailableNot Yet RecruitingTreatmentPatients With INOCA(Ischemia and no Obstructive Coronary Artery Disease) Who Have Coronary Microvascular Dysfunction1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP1.04 Reymond F, Steyaert G, Carrupt PA, Morin D, Tillement JP, Girault HH, Testa B. (1999). The pH-partition profile of the anti-ischemic drug trimetazidine may explain its reduction of intracellular acidosis. Pharm Res; 16(5):616-24.
pKapKa1= 4.45 ± 0.02 and pKa2= 9.14 ± 0.02Reymond F, Steyaert G, Carrupt PA, Morin D, Tillement JP, Girault HH, Testa B. (1999). The pH-partition profile of the anti-ischemic drug trimetazidine may explain its reduction of intracellular acidosis. Pharm Res; 16(5):616-24.
Predicted Properties
PropertyValueSource
Water Solubility0.754 mg/mLALOGPS
logP0.85ALOGPS
logP0.91ChemAxon
logS-2.6ALOGPS
pKa (Strongest Basic)9.21ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area42.96 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity74.75 m3·mol-1ChemAxon
Polarizability29.15 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-014i-2900000000-9af80d4cc6e8d3139dd7

Taxonomy

Description
This compound belongs to the class of organic compounds known as phenylmethylamines. These are compounds containing a phenylmethtylamine moiety, which consists of a phenyl group substituted by an methanamine.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Phenylmethylamines
Direct Parent
Phenylmethylamines
Alternative Parents
Phenoxy compounds / Methoxybenzenes / Benzylamines / Anisoles / N-alkylpiperazines / Aralkylamines / Alkyl aryl ethers / Trialkylamines / Dialkylamines / Azacyclic compounds
show 2 more
Substituents
Phenoxy compound / Anisole / Benzylamine / Phenol ether / Phenylmethylamine / Methoxybenzene / Alkyl aryl ether / Aralkylamine / N-alkylpiperazine / 1,4-diazinane
show 16 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Palmitoyl-coa oxidase activity
Specific Function
Not Available
Gene Name
ACAA1
Uniprot ID
P09110
Uniprot Name
3-ketoacyl-CoA thiolase, peroxisomal
Molecular Weight
44291.575 Da
References
  1. Kantor PF, Lucien A, Kozak R, Lopaschuk GD: The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res. 2000 Mar 17;86(5):580-8. [PubMed:10720420]

Drug created on May 12, 2015 15:45 / Updated on November 05, 2018 17:49