Basic information
- CAS
155974-00-8- Standard SMILES
COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C[C@H]1Cc3cc(OC)c(OC)cc31)CC2- InChIKey
ACRHBAYQBXXRTO-OAQYLSRUSA-N- Molecular formula
- C27H36N2O5
- Average molar mass
- 468.6 g/mol
- Monoisotopic mass
- 468.26242225
Overview
Ivabradine is a member of the class of benzazepines that is 7,8-dimethoxy-1,3,4,5-tetrahydro-3-benzazepin-2-one in which the amide hydrogen is replaced by a [{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino]propyl} group. Used (as its hydrochloride salt) to treat patients with angina who have intolerance to beta blockers and/or heart failure. It has a role as a cardiotonic drug. It is an aromatic ether, a benzazepine, a carbobicyclic compound and a tertiary amino compound. It is a conjugate base of an ivabradine(1+).
Names & identifiers
- Preferred name
- Ivabradine
- IUPAC
- 3-[3-[[(7S)-3,4-dimethoxy-7-bicyclo[4.2.0]octa-1,3,5-trienyl]methyl-methylamino]propyl]-7,8-dimethoxy-2,5-dihydro-1H-3-benzazepin-4-one
- English name
- Ivabradine
- Molecular formula
- C27H36N2O5
- Molecular weight
- 468.59
Names & synonyms
Ivabradine155974-00-8S-16257IvabradinaS 162573H48L0LPZQDTXSID20482403-[3-({[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino)propyl]-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-2-oneCHEBI:85966s16257(S)-3-(3-(((3,4-Dimethoxybicyclo(4.2.0)octa-1,3,5-trien-7-yl)methyl)methylamino)propyl)-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one2H-3-Benzazepin-2-one, 3-(3-(((3,4-dimethoxybicyclo(4.2.0)octa-1,3,5-trien-7-yl)methyl)methylamino)propyl)-1,3,4,5-tetrahydro-7,8-dimethoxy-, (S)-
Show more names
Ivabradine sulfateIvabridine –Ivabradine APIIvabradine USP/EP/BPIvabradine HCl PremixN-desmethyl ivabridine-d6Ivabradine(Hydrochloride form)3-[3-[[(8S)-3,4-dimethoxy-8-bicyclo[4.2.0]octa-1,3,5-trienyl]methyl-methyl-amino]propyl]-7,8-dimethoxy-2,5-dihydro-1H-3-benzazepin-4-one
Ivabradinum3-(3-((((7S)-3,4-dimethoxybicyclo(4.2.0)octa-1,3,5-trien-7-yl)methyl)(methyl)amino)propyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one3-(3-(((8S)-3,4-dimethoxy-8-bicyclo(4.2.0)octa-1,3,5-trienyl)methyl-methylamino)propyl)-7,8-dimethoxy-2,5-dihydro-1H-3-benzazepin-4-one3-[3-[[(8S)-3,4-dimethoxy-8-bicyclo[4.2.0]octa-1,3,5-trienyl]methyl-methylamino]propyl]-7,8-dimethoxy-2,5-dihydro-1H-3-benzazepin-4-oneRefChem:56735S162572S162602S 162572
Database identifiers
- CAS
155974-00-8- PubChem CID
- 132999
- DTXSID
DTXSID2048240- ChEMBL
CHEMBL471737- ChEBI
CHEBI:85966- UNII
- 3H48L0LPZQ
- Nikkaji
- J582.018I
Properties
Computed structural properties
- XLogP
- 2.4
- Topological polar surface area
- 60.5 Ų
- Hydrogen bond donors
- 0
- Hydrogen bond acceptors
- 6
- Rotatable bonds
- 10
- Heavy atoms
- 34
- Formal charge
- 0
- Complexity
- 663
Experimental & physicochemical properties
DrugsPharmaceuticals -> Listed in ZINC15
Human Drugs
Breast Feeding; Lactation; Milk, Human; Cardiovascular Agents
FDA approved drugs -> Active ingredient
EMA approved medicines: Human medicine
EMA approved medicines: Human medicine
EMA approved medicines: Human medicine
EMA approved medicines: Human medicine
Endocrine DisruptorsPotential endocrine disrupting compound
Physicochemical properties
- Boiling point
- 626.9 · 626.9±55.0 °C(Predicted)
- Density
- 1.146 · 1.146±0.06 g/cm3(Predicted)
- pka
- 8.77 · 8.77±0.50(Predicted)
- FDA UNII
- 3 H48L0LPZQ · 3H48L0LPZQ
- ATC code
- 1 EB17 · C01EB17
Safety & regulation
Toxicology
HepatotoxicityIn large preregistration clinical trials, similar proportions of patients taking ivabradine as taking placebo developed ALT elevations [15% vs 17%] while ALT elevations above 5 times the upper limit of normal were uncommon [
Adverse EffectsThe most common adverse effects associated with ivabradine administration, according to the product label, include bradycardia, atrial fibrillation, hypertension, and phosphenes.
Toxicity SummarySigns and Symptoms of Overdose
Effects During Pregnancy and Lactation◉ Summary of Use during Lactation
Chemistry & industry
Pharmacology
ATC Code
C01EB17
C - Cardiovascular system
QC - Cardiovascular system
Protein Binding70% bound to plasma proteins.
Pharmacodynamics
The funny channels (If) open during repolarization and close during depolarization, making ivabradine's activity dependent on heart rate or the closing and opening of the channels. Therefore ivabradine exhibits use-dependence and is more pharmacologically active at higher heart rates. Ivabradine exhibits a linear dose-dependent heart-rate lowering activity (bradycardic effect) until a maximum dose of 30-40mg. At higher doses, the concentration of ivabradine tends to plateau, reducing risk of serious sinus bradycardia. It has been shown that the metabolite of ivabradine lowers heart rate as well, contributing to ivabradine's overall effect.
Mechanism of Action
Ivabradine lowers heart rate by selectively inhibiting If channels ("funny channels") in the heart in a concentration-dependent manner without affecting any other cardiac ionic channels (including calcium or potassium). Ivabradine binds by entering and attaching to a site on the channel pore from the intracellular side and disrupts If ion current flow, which prolongs diastolic depolarization, lowering heart rate. The If currents are located in the sinoatrial node and are the home of all cardiac pacemaker activity. Ivabradine therefore lowers the pacemaker firing rate, consequently lowering heart rate and reducing myocardial oxygen demand. This allows for an improved oxygen supply and therefore mitigation of ischemia, allowing for a higher exercise capacity and reduction in angina episodes.
Biological Half-Life2 hours.
Metabolism/Metabolites
Ivabradine is extensively metabolized by oxidation in the gut and liver by cytochrome P450 3A4 enzyme. Its active metabolite, N-desmethylated derivative, is also metabolized by CYP 3A4. Ivabradine's affinity for CYP 3A4 is low, making it unlikely to affect the metabolism of other drugs; however potent inhibitors or inducers of CYP 3A4 may affect ivabradine's plasma concentration and pharmacodynamic effects and should not be co-administered.
FDA Pharmacological Classification
3H48L0LPZQ
IVABRADINE
Established Pharmacologic Class [EPC] - Hyperpolarization-activated Cyclic Nucleotide-gated Channel Blocker
Mechanisms of Action [MoA] - Hyperpolarization-activated Cyclic Nucleotide-gated Channel Antagonists
Ivabradine is a Hyperpolarization-activated Cyclic Nucleotide-gated Channel Blocker. The mechanism of action of ivabradine is as a Hyperpolarization-activated Cyclic Nucleotide-gated Channel Antagonist.
IVABRADINE
MeSH Pharmacological ClassificationAgents that affect the rate or intensity of cardiac contraction, blood vessel diameter, or blood volume.
Absorption, Distribution and Excretion
It is recommended to take ivabradine with food to reduce variability in systemic exposure. Administration with food slows absorption by 1 hour, but increases systemic absorption by 20-30%. Ivabradine's oral bioavailability is about 40%.
Metabolites are equally excreted in feces and urine.
~100 L.
Total clearance is about 400ml/min; renal clearance about 70ml/min. About 4% is excreted unchanged in urine.
Uses & manufacturing
UsesUse (kg; approx.) in Germany (2009): >75
Applications
DescriptionIvabradine is a first selective and specific If inhibitor that was approved by EMEA in November for symptomatic treatment of chronic stable angina pectoris in patients with normal sinus rhythm. This is the first agent to lower heart rate by inhibiting the cardiac pacemaker If current. The compound was discovered and developed by Servier and is currently being marketed in Ireland.
UsesIvabradine is a potent and orally active HCN (hyperpolarization-activated cyclic nucleotide-gated) channel blocker that inhibits the cardiac pacemaker current (If). Ivabradine reduces dose-dependently heart rate without modification of blood pressure. Ivabradine shows anticonvulsant, anti-ischaemic and anti-anginal activity[1][2][3][4].
Upstream & downstream products
Upstream raw materials
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Additional notes
DefinitionChEBI: A member of the class of benzazepines that is 7,8-dimethoxy-1,3,4,5-tetrahydro-3-benzazepin-2-one in which the amide hydrogen is replaced by a [{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino]propyl} group. Use (as its hydrochloride salt) to treat patients with angina who have intolerance to beta blockers and/or heart failure.
Related reactions
19 records
Compound notes
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