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Identification
NameAzimilide
Accession NumberDB04957
TypeSmall Molecule
GroupsInvestigational
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
SynonymsNot Available
External Identifiers Not Available
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
StedicorNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII74QU6P2934
CAS number149908-53-2
WeightAverage: 457.96
Monoisotopic: 457.1880675
Chemical FormulaC23H28ClN5O3
InChI KeyMREBEPTUUMTTIA-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
Taxonomy
DescriptionThis 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.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassAzolidines
Sub ClassImidazolidines
Direct ParentHydantoins
Alternative Parents
Substituents
  • Hydantoin
  • Alpha-amino acid or derivatives
  • Halobenzene
  • Ureide
  • N-methylpiperazine
  • N-alkylpiperazine
  • Chlorobenzene
  • Aryl chloride
  • 1,4-diazinane
  • Piperazine
  • Semicarbazone
  • Aryl halide
  • Monocyclic benzene moiety
  • Benzenoid
  • Dicarboximide
  • Heteroaromatic compound
  • Furan
  • Semicarbazide
  • Tertiary amine
  • Tertiary aliphatic amine
  • Amino acid or derivatives
  • Oxacycle
  • Carboxylic acid derivative
  • Azacycle
  • Organooxygen compound
  • Organic oxygen compound
  • Amine
  • Carbonyl group
  • Organic nitrogen compound
  • Hydrocarbon derivative
  • Organic oxide
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationInvestigated for use/treatment in arrhythmia and atrial fibrillation.
PharmacodynamicsAzimilide 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 actionThe 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.
Related Articles
AbsorptionExcellent oral absorption.
Volume of distributionNot Available
Protein bindingNot 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 eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot 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 RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
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
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot 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 complex. Assembled with KCNB1 modulates the gating characteristics of the delayed rectifier voltage-dependent potassium channel KCNB1 (PubMed:19219384). Assembled with KCNQ1/KVLQT1 is proposed to for...
Gene Name:
KCNE1
Uniprot ID:
P15382
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 modulates current kinetics (By similarity) (PubMed:9312006, PubMed:9108097, PubMed:8900283, PubMed:10646604, PubMed:11101505, PubMed:19687231). Induces a voltage-dependent by rapidly activating and slowly ...
Gene Name:
KCNQ1
Uniprot ID:
P51787
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 delayed rectifying potassium current in heart (IKr). Isoforms USO have no channel activity by themself, but modulates channel characteristics by forming heterotetramers with other isoforms which are r...
Gene Name:
KCNH2
Uniprot ID:
Q12809
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 unrelated compounds, including steroids, fatty acids, and xenobiotics.
Gene Name:
CYP1A1
Uniprot ID:
P04798
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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
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 unrelated compounds, including steroids, fatty acids, and xenobiotics.
Gene Name:
CYP3A5
Uniprot ID:
P20815
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 ]
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Drug created on October 21, 2007 16:23 / Updated on August 17, 2016 12:24