Identification

Name
Moricizine
Accession Number
DB00680  (APRD01124)
Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
Description

An antiarrhythmia agent used primarily for ventricular rhythm disturbances. [PubChem]

Structure
Thumb
Synonyms
  • [10-(3-Morpholin-4-yl-propionyl)-10H-phenothiazin-2-yl]-carbamic acid ethyl ester
  • EN-313
  • Ethmozin
  • Ethyl 10-(3-morpholinopropionyl)phenothiazine-2-carbamate
  • Ethyl 10-(beta-N-morpholinylpropionyl)phenothiazine-2-carbamate
  • Etmozin
  • Moracizin
  • Moracizina
  • Moracizine
  • Moracizinum
  • Moricizine
External IDs
EN-313 / G 214
Product Ingredients
IngredientUNIICASInChI Key
moricizine hydrochloride71OK3Z1ESP29560-58-5GAQAKFHSULJNAK-UHFFFAOYSA-N
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
EthmozineTablet200 mg/1OralShire1990-06-192008-08-07Us
EthmozineTablet300 mg/1OralShire1990-06-192008-08-07Us
EthmozineTablet250 mg/1OralShire1990-06-192008-08-07Us54092 04720180907 15195 di0ahn
International/Other Brands
Ethmozine / Etmozins (Olainfarm)
Categories
UNII
2GT1D0TMX1
CAS number
31883-05-3
Weight
Average: 427.517
Monoisotopic: 427.156576993
Chemical Formula
C22H25N3O4S
InChI Key
FUBVWMNBEHXPSU-UHFFFAOYSA-N
InChI
InChI=1S/C22H25N3O4S/c1-2-29-22(27)23-16-7-8-20-18(15-16)25(17-5-3-4-6-19(17)30-20)21(26)9-10-24-11-13-28-14-12-24/h3-8,15H,2,9-14H2,1H3,(H,23,27)
IUPAC Name
ethyl N-{10-[3-(morpholin-4-yl)propanoyl]-10H-phenothiazin-2-yl}carbamate
SMILES
CCOC(=O)NC1=CC2=C(SC3=CC=CC=C3N2C(=O)CCN2CCOCC2)C=C1

Pharmacology

Indication

Used to treat irregular heartbeats (arrhythmias) and maintain a normal heart rate.

Pharmacodynamics

Moricizine is used to treat irregular heartbeats (arrhythmias) and to maintain a normal heart rate. It acts on the heart muscle to improve the heart's rhythm. Moricizine has potent local anesthetic activity and membrane stabilizing effect. Decreases excitability, conduction velocity, and automaticity as a result of slowed atrioventricular (AV) nodal and His-Purkinje conduction. Decreases the action potential duration (APD) in Purkinje fibers; also decreases the effective refractory period (ERP) but to a lesser extent than the APD, so the ERP/APD ratio is increased. Decreases the maxiumum rate of Phase 0 depolarization (V max ), but does not affect action potential amplitude or maximum diastolic potential. Does not affect atrial, AV nodal, or left ventricular refractory periods and has minimal effect on ventricular repolarization (evidenced by the overall decrease in JT interval). Has no effect on sinoatrial (SA) nodal or intra-atrial conduction and only minimal effect on sinus cycle length and sinus node recovery time. In the Vaughan Williams classification of antiarrhythmics, moricizine is considered to be a class I agent. It has properties of class IA, IB, and IC agents but does not clearly belong to any of the three subclasses. It has less effect on the slope of phase 0 and a greater effect on action potential duration and effective refractory period than class IC agents.

Mechanism of action

Moricizine works by inhibiting the rapid inward sodium current across myocardial cell membranes.

TargetActionsOrganism
ASodium channel protein type 5 subunit alpha
inhibitor
Human
Absorption

Well absorbed, absorption is complete within 2 to 3 hours. Significant first-pass metabolism results in an absolute bioavailability of approximately 38%. Administration within 30 minutes after a meal slows the rate, but does not affect the extent of absorption, although peak plasma concentrations are reduced.

Volume of distribution
  • 300 L
Protein binding

Approximately 95%.

Metabolism

Hepatic and extensive, to at least 26 metabolites, none accounting for as much as 1% of the administered dose. Two metabolites may be pharmacologically active but are present in extremely small quantities. Moricizine induces its own metabolism (it induces hepatic cytochrome P-450 activity).

Route of elimination

Less than 1% of orally administered Ethmozine® is excreted unchanged in the urine. Approximately 56% of the administered dose is excreted in the feces and 39% is excreted in the urine.

Half life

2 hours (range 1.5-3.5 hours).

Clearance
Not Available
Toxicity

Symptoms of overdose include vomiting, unconsciousness, and severe low blood pressure.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
2,5-Dimethoxy-4-ethylamphetamineMoricizine may decrease the stimulatory activities of 2,5-Dimethoxy-4-ethylamphetamine.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Moricizine is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetamineMoricizine may decrease the stimulatory activities of 3,4-Methylenedioxyamphetamine.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when Moricizine is combined with 4-Bromo-2,5-dimethoxyamphetamine.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when Moricizine is combined with 4-Methoxyamphetamine.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of adverse effects can be increased when Moricizine is combined with 5-methoxy-N,N-dimethyltryptamine.
7-NitroindazoleThe risk or severity of adverse effects can be increased when Moricizine is combined with 7-Nitroindazole.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolineThe risk or severity of adverse effects can be increased when Moricizine is combined with 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline.
AbexinostatThe risk or severity of QTc prolongation can be increased when Moricizine is combined with Abexinostat.
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Moricizine.
Food Interactions
Not Available

References

Synthesis Reference
US3740395A
General References
Not Available
External Links
Human Metabolome Database
HMDB0014818
KEGG Drug
D05077
KEGG Compound
C07743
PubChem Compound
34633
PubChem Substance
46509072
ChemSpider
31872
ChEBI
6997
ChEMBL
CHEMBL1075
Therapeutic Targets Database
DAP000510
PharmGKB
PA164747738
Drugs.com
Drugs.com Drug Page
Wikipedia
Moricizine
ATC Codes
C01BG01 — Moracizine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentArrhythmia of ventricular origin / Arrythmias / Cardiovascular Disease (CVD) / Heart Diseases1
3CompletedPreventionArrhythmia of ventricular origin / Cardiovascular Disease (CVD) / Coronary Heart Disease (CHD) / Death, Sudden,Cardiac / Heart Arrest / Heart Diseases / Myocardial Infarction / Myocardial Ischemia1
3CompletedTreatmentArrythmias / Cardiovascular Disease (CVD) / Heart Diseases / Nonvalvular Atrial Fibrillation1

Pharmacoeconomics

Manufacturers
  • Shire development inc
Packagers
  • Bristol-Myers Squibb Co.
Dosage forms
FormRouteStrength
TabletOral200 mg/1
TabletOral250 mg/1
TabletOral300 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)156-157 °CPhysProp
water solubility0.457 mg/LNot Available
logP2.98SANGSTER (1994)
Predicted Properties
PropertyValueSource
Water Solubility0.0339 mg/mLALOGPS
logP3.04ALOGPS
logP3.07ChemAxon
logS-4.1ALOGPS
pKa (Strongest Acidic)12.9ChemAxon
pKa (Strongest Basic)6.73ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area71.11 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity118.88 m3·mol-1ChemAxon
Polarizability45.27 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9885
Blood Brain Barrier+0.9535
Caco-2 permeable-0.5796
P-glycoprotein substrateSubstrate0.6871
P-glycoprotein inhibitor IInhibitor0.9072
P-glycoprotein inhibitor IINon-inhibitor0.5751
Renal organic cation transporterNon-inhibitor0.8329
CYP450 2C9 substrateNon-substrate0.7472
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateNon-substrate0.5274
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.6367
CYP450 2D6 inhibitorNon-inhibitor0.923
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorInhibitor0.7959
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.7638
Ames testNon AMES toxic0.6915
CarcinogenicityNon-carcinogens0.9153
BiodegradationNot ready biodegradable0.8412
Rat acute toxicity2.4731 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9229
hERG inhibition (predictor II)Inhibitor0.732
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

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

Taxonomy

Description
This compound belongs to the class of organic compounds known as phenothiazines. These are polycyclic aromatic compounds containing a phenothiazine moiety, which is a linear tricyclic system that consists of a two benzene rings joined by a para-thiazine ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzothiazines
Sub Class
Phenothiazines
Direct Parent
Phenothiazines
Alternative Parents
Diarylthioethers / Beta amino acids and derivatives / 1,4-thiazines / Morpholines / Benzenoids / Tertiary carboxylic acid amides / Trialkylamines / Propargyl-type 1,3-dipolar organic compounds / Oxacyclic compounds / Azacyclic compounds
show 6 more
Substituents
Phenothiazine / Beta amino acid or derivatives / Diarylthioether / Aryl thioether / Para-thiazine / Morpholine / Oxazinane / Benzenoid / Tertiary carboxylic acid amide / Amino acid or derivatives
show 22 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
phenothiazines, carbamate ester, morpholines (CHEBI:6997)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated sodium channel activity involved in sa node cell action potential
Specific Function
This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the pr...
Gene Name
SCN5A
Uniprot ID
Q14524
Uniprot Name
Sodium channel protein type 5 subunit alpha
Molecular Weight
226937.475 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
  3. Ahmmed GU, Hisatome I, Kurata Y, Makita N, Tanaka Y, Tanaka H, Okamura T, Sonoyama K, Furuse Y, Kato M, Yamamoto Y, Ogura K, Shimoyama M, Miake J, Sasaki N, Ogino K, Igawa O, Yoshida A, Shigemasa C: Analysis of moricizine block of sodium current in isolated guinea-pig atrial myocytes. Atrioventricular difference of moricizine block. Vascul Pharmacol. 2002 Mar;38(3):131-41. [PubMed:12402511]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 08:44