Identification

Name
Azimilide
Accession Number
DB04957
Type
Small Molecule
Groups
Investigational
Description

Azimilide is an investigational class III anti-arrhythmic drug that blocks fast and slow components of the delayed rectifier cardiac potassium channels. It is not approved for use in any country, but is currently in clinical trials in the United States.

Structure
Thumb
Synonyms
Not Available
International/Other Brands
Stedicor
Categories
UNII
74QU6P2934
CAS number
149908-53-2
Weight
Average: 457.96
Monoisotopic: 457.1880675
Chemical Formula
C23H28ClN5O3
InChI Key
MREBEPTUUMTTIA-UHFFFAOYSA-N
InChI
InChI=1S/C23H28ClN5O3/c1-26-12-14-27(15-13-26)10-2-3-11-28-22(30)17-29(23(28)31)25-16-20-8-9-21(32-20)18-4-6-19(24)7-5-18/h4-9,16H,2-3,10-15,17H2,1H3
IUPAC Name
1-({[5-(4-chlorophenyl)furan-2-yl]methylidene}amino)-3-[4-(4-methylpiperazin-1-yl)butyl]imidazolidine-2,4-dione
SMILES
CN1CCN(CCCCN2C(=O)CN(N=CC3=CC=C(O3)C3=CC=C(Cl)C=C3)C2=O)CC1

Pharmacology

Indication

Investigated for use/treatment in arrhythmia and atrial fibrillation.

Pharmacodynamics

Azimilide is a new class III anti-arrhythmic agent. It is distinguished by a relative lack of reverse use-dependence, excellent oral absorption, no need for dose titration, an option for out-patient initiation, no need for adjustment associated with renal or liver failure and a lack of interaction with warfarin or digoxin. It carries some risk of torsade de pointes and rarely, neutropoenia.

Mechanism of action

The mechanism of action of azimilide is to block both the slowly conducting (I(Ks)) and rapidly conducting (I(Kr)) rectifier potassium currents in cardiac cells. This differs from other class III agents that block I(Kr) exclusively or in combination with sodium, calcium, or transient outward (I(to)) potassium current channels. It also has blocking effects on sodium (I(Na)) and calcium currents (I(CaL)). Its effects on reentrant circuits in infarct border zones causing ventricular tachyarrhythmias are unknown.

TargetActionsOrganism
UPotassium voltage-gated channel subfamily E member 1Not AvailableHuman
UPotassium voltage-gated channel subfamily KQT member 1Not AvailableHuman
UPotassium voltage-gated channel subfamily H member 2Not AvailableHuman
Absorption

Excellent oral absorption.

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

The metabolic fate of azimilide in man is unusual as it undergoes a cleavage in vivo resulting in the formation of two classes of structurally distinct metabolites. One study has shown that a cleaved metabolite, 4-chloro-2-phenyl furoic acid was present at high concentration in plasma, while other plasma metabolites, azimilide N-oxide, and a cleaved hydantoin metabolite were present at lower concentrations than azimilide. In urine, the cleaved metabolites were the major metabolites, (> 35% of the dose) along with phenols (as conjugates, 7%-8%), azimilide N-oxide (4%-10%), a butanoic acid metabolite (2%-3%), and desmethyl azimilide (2%). A limited investigation of fecal metabolites indicated that azimilide (3%-5%), desmethyl azimilide (1%-3%), and the butanoic acid metabolite (< 1%) were present. Contributing pathways for metabolism of azimilide, identified through in vitro and in-vivo studies, were CYPs 1A1 (est. 28%), 3A4/5 (est. 20%), 2D6 (< 1%), FMO (est. 14%), and cleavage (35%). Enzyme(s) involved in the cleavage of azimilide were not identified.

Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
2-mercaptobenzothiazoleThe therapeutic efficacy of 2-mercaptobenzothiazole can be increased when used in combination with Azimilide.
AcepromazineThe risk or severity of hypotension can be increased when Acepromazine is combined with Azimilide.
AlfuzosinThe risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Azimilide.
AmitriptylineThe risk or severity of QTc prolongation can be increased when Amitriptyline is combined with Azimilide.
AmobarbitalThe metabolism of Azimilide can be increased when combined with Amobarbital.
AmorolfineThe therapeutic efficacy of Amorolfine can be increased when used in combination with Azimilide.
AmoxapineThe risk or severity of hypotension can be increased when Amoxapine is combined with Azimilide.
Amphotericin BThe therapeutic efficacy of Amphotericin B can be increased when used in combination with Azimilide.
AnagrelideThe risk or severity of QTc prolongation can be increased when Azimilide is combined with Anagrelide.
AnidulafunginThe therapeutic efficacy of Anidulafungin can be increased when used in combination with Azimilide.
Food Interactions
Not Available

References

General References
  1. Schmitt H, Cabo C, Coromilas JC, Wit AL: Effects of azimilide, a new class III antiarrhythmic drug, on reentrant circuits causing ventricular tachycardia and fibrillation in a canine model of myocardial infarction. J Cardiovasc Electrophysiol. 2001 Sep;12(9):1025-33. [PubMed:11573692]
  2. Abrol R, Page RL: Azimilide dihydrochloride: a new class III anti-arrhythmic agent. Expert Opin Investig Drugs. 2000 Nov;9(11):2705-15. [PubMed:11060832]
  3. Tran HT: Azimilide dihydrochloride: a unique class III antiarrhythmic agent. Heart Dis. 1999 May-Jun;1(2):114-6. [PubMed:11720612]
  4. Toothaker RD, Corey AE, Valentine SN, Agnew JR, Parekh N, Moehrke W, Thompson GA, Powell JH: Influence of coadministration on the pharmacokinetics of azimilide dihydrochloride and digoxin. J Clin Pharmacol. 2005 Jul;45(7):773-80. [PubMed:15951467]
  5. Riley P, Figary PC, Entwisle JR, Roe AL, Thompson GA, Ohashi R, Ohashi N, Moorehead TJ: The metabolic profile of azimilide in man: in vivo and in vitro evaluations. J Pharm Sci. 2005 Sep;94(9):2084-95. [PubMed:16052551]
External Links
KEGG Compound
C13777
PubChem Compound
9571004
PubChem Substance
175426919
ChemSpider
54906
BindingDB
50117913
Wikipedia
Azimilide

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3TerminatedTreatmentCardiac Dysrhythmia / Cardiovascular Disease (CVD) / Heart Diseases / Implantable Cardioverter Defibrillator (ICD)1

Pharmacoeconomics

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

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0861 mg/mLALOGPS
logP2.91ALOGPS
logP2.59ChemAxon
logS-3.7ALOGPS
pKa (Strongest Acidic)11.95ChemAxon
pKa (Strongest Basic)8.7ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area72.6 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity124.83 m3·mol-1ChemAxon
Polarizability50.15 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9013
Caco-2 permeable-0.5057
P-glycoprotein substrateSubstrate0.7072
P-glycoprotein inhibitor IInhibitor0.79
P-glycoprotein inhibitor IINon-inhibitor0.5948
Renal organic cation transporterInhibitor0.614
CYP450 2C9 substrateNon-substrate0.7463
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateSubstrate0.7085
CYP450 1A2 substrateNon-inhibitor0.8317
CYP450 2C9 inhibitorNon-inhibitor0.7377
CYP450 2D6 inhibitorNon-inhibitor0.8987
CYP450 2C19 inhibitorInhibitor0.5383
CYP450 3A4 inhibitorNon-inhibitor0.8177
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8234
Ames testAMES toxic0.5429
CarcinogenicityNon-carcinogens0.7114
BiodegradationNot ready biodegradable0.9967
Rat acute toxicity2.6412 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.8037
hERG inhibition (predictor II)Inhibitor0.5718
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 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 hydantoins. These are heterocyclic compounds containing an imidazolidine substituted by ketone group at positions 2 and 4.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Azolidines
Sub Class
Imidazolidines
Direct Parent
Hydantoins
Alternative Parents
Alpha amino acids and derivatives / N-methylpiperazines / Chlorobenzenes / Semicarbazones / Aryl chlorides / Heteroaromatic compounds / Furans / Dicarboximides / Trialkylamines / Organic carbonic acids and derivatives
show 7 more
Substituents
Hydantoin / Alpha-amino acid or derivatives / Chlorobenzene / Halobenzene / N-methylpiperazine / N-alkylpiperazine / Aryl chloride / Aryl halide / Monocyclic benzene moiety / 1,4-diazinane
show 26 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Telethonin binding
Specific Function
Ancillary protein that assembles as a beta subunit with a voltage-gated potassium channel complex of pore-forming alpha subunits. Modulates the gating kinetics and enhances stability of the channel...
Gene Name
KCNE1
Uniprot ID
P15382
Uniprot Name
Potassium voltage-gated channel subfamily E member 1
Molecular Weight
14674.66 Da
References
  1. Schmitt H, Cabo C, Coromilas JC, Wit AL: Effects of azimilide, a new class III antiarrhythmic drug, on reentrant circuits causing ventricular tachycardia and fibrillation in a canine model of myocardial infarction. J Cardiovasc Electrophysiol. 2001 Sep;12(9):1025-33. [PubMed:11573692]
  2. Abrol R, Page RL: Azimilide dihydrochloride: a new class III anti-arrhythmic agent. Expert Opin Investig Drugs. 2000 Nov;9(11):2705-15. [PubMed:11060832]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function
Potassium channel that plays an important role in a number of tissues, including heart, inner ear, stomach and colon (By similarity) (PubMed:10646604). Associates with KCNE beta subunits that modul...
Gene Name
KCNQ1
Uniprot ID
P51787
Uniprot Name
Potassium voltage-gated channel subfamily KQT member 1
Molecular Weight
74697.925 Da
References
  1. Schmitt H, Cabo C, Coromilas JC, Wit AL: Effects of azimilide, a new class III antiarrhythmic drug, on reentrant circuits causing ventricular tachycardia and fibrillation in a canine model of myocardial infarction. J Cardiovasc Electrophysiol. 2001 Sep;12(9):1025-33. [PubMed:11573692]
  2. Abrol R, Page RL: Azimilide dihydrochloride: a new class III anti-arrhythmic agent. Expert Opin Investig Drugs. 2000 Nov;9(11):2705-15. [PubMed:11060832]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function
Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the ...
Gene Name
KCNH2
Uniprot ID
Q12809
Uniprot Name
Potassium voltage-gated channel subfamily H member 2
Molecular Weight
126653.52 Da
References
  1. Schmitt H, Cabo C, Coromilas JC, Wit AL: Effects of azimilide, a new class III antiarrhythmic drug, on reentrant circuits causing ventricular tachycardia and fibrillation in a canine model of myocardial infarction. J Cardiovasc Electrophysiol. 2001 Sep;12(9):1025-33. [PubMed:11573692]
  2. Abrol R, Page RL: Azimilide dihydrochloride: a new class III anti-arrhythmic agent. Expert Opin Investig Drugs. 2000 Nov;9(11):2705-15. [PubMed:11060832]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Vitamin d 24-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A1
Uniprot ID
P04798
Uniprot Name
Cytochrome P450 1A1
Molecular Weight
58164.815 Da
References
  1. Riley P, Figary PC, Entwisle JR, Roe AL, Thompson GA, Ohashi R, Ohashi N, Moorehead TJ: The metabolic profile of azimilide in man: in vivo and in vitro evaluations. J Pharm Sci. 2005 Sep;94(9):2084-95. [PubMed:16052551]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Riley P, Figary PC, Entwisle JR, Roe AL, Thompson GA, Ohashi R, Ohashi N, Moorehead TJ: The metabolic profile of azimilide in man: in vivo and in vitro evaluations. J Pharm Sci. 2005 Sep;94(9):2084-95. [PubMed:16052551]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Riley P, Figary PC, Entwisle JR, Roe AL, Thompson GA, Ohashi R, Ohashi N, Moorehead TJ: The metabolic profile of azimilide in man: in vivo and in vitro evaluations. J Pharm Sci. 2005 Sep;94(9):2084-95. [PubMed:16052551]

Drug created on October 21, 2007 16:23 / Updated on August 02, 2018 05:28