Identification
- Generic Name
- Azimilide
- DrugBank Accession Number
- DB04957
- Background
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.
- Type
- Small Molecule
- Groups
- Investigational
- Structure
Structure for Azimilide (DB04957)
- Weight
- Average: 457.96
Monoisotopic: 457.1880675 - Chemical Formula
- C23H28ClN5O3
- Synonyms
- Azimilide
Pharmacology
- Indication
Investigated for use/treatment in arrhythmia and atrial fibrillation.
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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.
Target Actions Organism UPotassium voltage-gated channel subfamily E member 1 Not Available Humans UPotassium voltage-gated channel subfamily KQT member 1 Not Available Humans UPotassium voltage-gated channel subfamily H member 2 Not Available Humans - 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
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Not Available
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Azimilide can be increased when it is combined with Abametapir. Abatacept The metabolism of Azimilide can be increased when combined with Abatacept. Acalabrutinib The metabolism of Azimilide can be decreased when combined with Acalabrutinib. Acebutolol Acebutolol may increase the arrhythmogenic activities of Azimilide. Acetyldigitoxin Acetyldigitoxin may increase the arrhythmogenic activities of Azimilide. - Food Interactions
- Not Available
Products
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- Stedicor
Categories
- Drug Categories
- Antiarrhythmic agents
- Antiarrhythmics, Class III
- Calcium-Regulating Hormones and Agents
- Cardiovascular Agents
- Cytochrome P-450 CYP2D6 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A5 Substrates
- Cytochrome P-450 Substrates
- Imidazoles
- Imidazolidines
- Membrane Transport Modulators
- Moderate Risk QTc-Prolonging Agents
- QTc Prolonging Agents
- Chemical TaxonomyProvided by Classyfire
- 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
- 1,4-diazinane / Alpha-amino acid or derivatives / Amine / Amino acid or derivatives / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid / Carbonic acid derivative show 26 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 74QU6P2934
- CAS number
- 149908-53-2
- 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
References
- General References
- 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. [Article]
- Abrol R, Page RL: Azimilide dihydrochloride: a new class III anti-arrhythmic agent. Expert Opin Investig Drugs. 2000 Nov;9(11):2705-15. [Article]
- Tran HT: Azimilide dihydrochloride: a unique class III antiarrhythmic agent. Heart Dis. 1999 May-Jun;1(2):114-6. [Article]
- 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. [Article]
- 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. [Article]
- External Links
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Terminated Treatment Arrhythmia / Cardiovascular Disease (CVD) / Implantable Cardioverter-defibrillators (ICDs) 1 2 Completed Treatment Congestive Heart Failure (CHF) 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
Property Value Source Water Solubility 0.0861 mg/mL ALOGPS logP 2.91 ALOGPS logP 2.59 Chemaxon logS -3.7 ALOGPS pKa (Strongest Acidic) 11.95 Chemaxon pKa (Strongest Basic) 8.7 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 0 Chemaxon Polar Surface Area 72.6 Å2 Chemaxon Rotatable Bond Count 8 Chemaxon Refractivity 124.83 m3·mol-1 Chemaxon Polarizability 50.15 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 1.0 Blood Brain Barrier + 0.9013 Caco-2 permeable - 0.5057 P-glycoprotein substrate Substrate 0.7072 P-glycoprotein inhibitor I Inhibitor 0.79 P-glycoprotein inhibitor II Non-inhibitor 0.5948 Renal organic cation transporter Inhibitor 0.614 CYP450 2C9 substrate Non-substrate 0.7463 CYP450 2D6 substrate Non-substrate 0.9116 CYP450 3A4 substrate Substrate 0.7085 CYP450 1A2 substrate Non-inhibitor 0.8317 CYP450 2C9 inhibitor Non-inhibitor 0.7377 CYP450 2D6 inhibitor Non-inhibitor 0.8987 CYP450 2C19 inhibitor Inhibitor 0.5383 CYP450 3A4 inhibitor Non-inhibitor 0.8177 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8234 Ames test AMES toxic 0.5429 Carcinogenicity Non-carcinogens 0.7114 Biodegradation Not ready biodegradable 0.9967 Rat acute toxicity 2.6412 LD50, mol/kg Not applicable hERG inhibition (predictor I) Strong inhibitor 0.8037 hERG inhibition (predictor II) Inhibitor 0.5718
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0a4i-0001900000-d6b94864bd072876b898 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0a4i-1020900000-e16e1665fcd06443ad9d Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0a4i-0011900000-0739559a25ca8fb83c59 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0041-4130900000-1b165214dfe61dcd398c Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-001i-0642900000-c660df6270a61837ce91 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-005a-5570900000-400bc71090565eda8e85 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 205.80943 predictedDeepCCS 1.0 (2019) [M+H]+ 208.16743 predictedDeepCCS 1.0 (2019) [M+Na]+ 214.94151 predictedDeepCCS 1.0 (2019)
Targets
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- Kind
- Protein
- Organism
- Humans
- 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
- 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. [Article]
- Abrol R, Page RL: Azimilide dihydrochloride: a new class III anti-arrhythmic agent. Expert Opin Investig Drugs. 2000 Nov;9(11):2705-15. [Article]
- Kind
- Protein
- Organism
- Humans
- 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
- 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. [Article]
- Abrol R, Page RL: Azimilide dihydrochloride: a new class III anti-arrhythmic agent. Expert Opin Investig Drugs. 2000 Nov;9(11):2705-15. [Article]
- Kind
- Protein
- Organism
- Humans
- 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
- 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. [Article]
- Abrol R, Page RL: Azimilide dihydrochloride: a new class III anti-arrhythmic agent. Expert Opin Investig Drugs. 2000 Nov;9(11):2705-15. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
- Gene Name
- CYP2D6
- Uniprot ID
- P10635
- Uniprot Name
- Cytochrome P450 2D6
- Molecular Weight
- 55768.94 Da
References
- 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. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- 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
- 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. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- 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
- 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. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- 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
- 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. [Article]
Drug created at October 21, 2007 22:23 / Updated at February 21, 2021 18:51