Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C27H36N2O5 |
Molecular Weight | 468.5851 |
Optical Activity | ( + ) |
Defined Stereocenters | 1 / 1 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
COC1=CC2=C(C=C1OC)[C@@H](CN(C)CCCN3CCC4=CC(OC)=C(OC)C=C4CC3=O)C2
InChI
InChIKey=ACRHBAYQBXXRTO-OAQYLSRUSA-N
InChI=1S/C27H36N2O5/c1-28(17-21-11-20-14-25(33-4)26(34-5)16-22(20)21)8-6-9-29-10-7-18-12-23(31-2)24(32-3)13-19(18)15-27(29)30/h12-14,16,21H,6-11,15,17H2,1-5H3/t21-/m1/s1
Molecular Formula | C27H36N2O5 |
Molecular Weight | 468.5851 |
Charge | 0 |
Count |
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Stereochemistry | ABSOLUTE |
Additional Stereochemistry | No |
Defined Stereocenters | 1 / 1 |
E/Z Centers | 0 |
Optical Activity | UNSPECIFIED |
DescriptionCurator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/16451297
Curator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/16451297
Ivabradine (CORLANOR®) is a hyperpolarization-activated cyclic nucleotide-gated channel blocker that reduces the spontaneous pacemaker activity of the cardiac sinus node by selectively inhibiting the If-current, resulting in heart rate reduction at concentrations that do not affect other cardiac ionic currents. Specific heart-rate lowering with ivabradine (CORLANOR®) reduces myocardial oxygen demand, simultaneously improving oxygen supply. It has no negative inotropic or lusitropic effects, preserving ventricular contractility, and does not change any major electrophysiological parameters unrelated to heart rate.
CNS Activity
Curator's Comment: Ivabradine (CORLANOR®) can also inhibit the retinal current Ih. Ih is involved in curtailing retinal responses to bright light stimuli. Under triggering circumstances (e.g., rapid changes in luminosity), partial inhibition of Ih by ivabradine (CORLANOR®) may underlie the luminous phenomena experienced by patients. Luminous phenomena (phosphenes) are described as a transient enhanced brightness in a limited area of the visual field.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL1795171 |
2.05 µM [IC50] | ||
Target ID: CHEMBL1795172 |
2.29 µM [IC50] | ||
Target ID: CHEMBL1795173 |
2.51 µM [IC50] | ||
Target ID: CHEMBL1250417 |
2.15 µM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Palliative | CORLANOR Approved UseCorlanor is indicated to reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction ≤ 35%, who are in sinus rhythm with resting heart rate ≥ 70 beats per minute and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use. Corlanor (ivabradine) is a hyperpolarization-activated cyclic nucleotide-gated channel blocker indicated to reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction ≤ 35%, who are in sinus rhythm with resting heart rate ≥ 70 beats per minute and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use. Launch Date2015 |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
35.98 ng/mL EXPERIMENT https://doi.org/10.1016/j.apsb.2012.01.004 |
5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered: |
IVABRADINE blood | Homo sapiens population: HEALTHY age: UNKNOWN sex: FEMALE / MALE food status: UNKNOWN |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
171.19 ng × h/mL EXPERIMENT https://doi.org/10.1016/j.apsb.2012.01.004 |
5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered: |
IVABRADINE blood | Homo sapiens population: HEALTHY age: UNKNOWN sex: FEMALE / MALE food status: UNKNOWN |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
5.03 h EXPERIMENT https://doi.org/10.1016/j.apsb.2012.01.004 |
5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered: |
IVABRADINE blood | Homo sapiens population: HEALTHY age: UNKNOWN sex: FEMALE / MALE food status: UNKNOWN |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
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OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
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Drug as perpetrator
Drug as victim
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206143Orig1s000PharmR.pdf#page=57 Page: 57.0 |
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Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206143Orig1s000PharmR.pdf#page=57 Page: 57.0 |
PubMed
Title | Date | PubMed |
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New agent ivabradine (Procoralan) for treatment of chronic stable angina. | 2005 Sep-Oct |
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[Ivabradin (coraxan). One more new approach to fighting myocardial ischemia in patients with ischemic heart disease]. | 2006 |
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[Why it is necessary to reduce heart rate in the treatment of stable angina?]. | 2006 |
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[Ivabradine--the first selective and specific I(f) inhibitor, novel preparation for treatment of stable angina]. | 2006 |
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Future directions: what data do we need? | 2006 |
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Heart rate slowing for myocardial dysfunction/heart failure. | 2006 |
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Novel If current inhibitor ivabradine: safety considerations. | 2006 |
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Heart rate slowing versus other pharmacological antianginal strategies. | 2006 |
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Clinical effect of 'pure' heart rate slowing with a prototype If current inhibitor: placebo-controlled experience with ivabradine. | 2006 |
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Clinical perspectives of heart rate slowing for coronary event reduction and heart failure. | 2006 |
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Heart rate reduction by pharmacological If current inhibition. | 2006 |
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If current inhibition: cellular basis and physiology. | 2006 |
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[A new medicine for treatment of stable angina pectoris]. | 2006 |
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[Heart rate reduction as a therapeutic strategy: novel options]. | 2006 Dec |
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Comparison of a beta-blocker and an If current inhibitor in rabbits with myocardial infarction. | 2006 Dec |
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[New drugs; ivabradine]. | 2006 Dec 2 |
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[Selective I(f) channel inhibition: an alternative for treating coronary artery disease?]. | 2006 Feb |
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Evolving treatment strategies for chronic refractory angina. | 2006 Feb |
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[The best of clinical cardiovascular pharmacology in 2005]. | 2006 Jan |
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Selective and specific I(f) inhibition: new perspectives for the treatment of stable angina. | 2006 Jun |
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[Possibilities of reducing heart rate by I(f)-channel inhibitors]. | 2006 Mar 22 |
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Anti-ischaemic effect of ivabradine. | 2006 May |
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Therapeutic effects of I(f) blockade: evidence and perspective. | 2006 May |
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Ivabradine: a selective If current inhibitor in the treatment of stable angina. | 2006 Nov |
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Rationale and design of a randomized, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease and left ventricular systolic dysfunction: the morBidity-mortality EvAlUaTion of the I(f) inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) study. | 2006 Nov |
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[Ivabradine--a medical alternative for patients with chronic stable angina pectoris]. | 2006 Nov 13 |
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Heart rate lowering by inhibition of the pacemaker current: a new therapeutic perspective in cardiovascular disease. | 2006 Oct |
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Lack of pharmacokinetic interaction between omeprazole or lansoprazole and ivabradine in healthy volunteers: an open-label, randomized, crossover, pharmacokinetic interaction clinical trial. | 2006 Oct |
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Effects of Hypericum perforatum on ivabradine pharmacokinetics in healthy volunteers: an open-label, pharmacokinetic interaction clinical trial. | 2006 Oct |
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Perspectives of I(f) inhibition by ivabradine in cardiology. | 2007 |
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Clinical results of I(f) current inhibition by ivabradine. | 2007 |
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Preclinical results with I(f) current inhibition by ivabradine. | 2007 |
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The funny current: cellular basis for the control of heart rate. | 2007 |
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If inhibition by Ivabradine. Foreword. | 2007 |
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Molecular regulation and pharmacology of pacemaker channels. | 2007 |
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I(f) current and heart rate control. | 2007 Apr |
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Selective inhibition of the pacemaker channel I(f) improves symptoms in severe dilated cardiomyopathy. | 2007 Apr |
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Heart rate reduction via selective 'funny' channel blockers. | 2007 Apr |
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Symptom improvement in postural orthostatic tachycardia syndrome with the sinus node blocker ivabradine. | 2007 Dec |
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Cellular mechanisms underlying the pharmacological induction of phosphenes. | 2007 Feb |
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Heart rate reduction by inhibition of If or by beta-blockade has different effects on postsystolic wall thickening. | 2007 Feb |
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Use-dependent inhibition of hHCN4 by ivabradine and relationship with reduction in pacemaker activity. | 2007 Jan |
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[Selective and specific reduction in the heart rate: a promising direction in the creation of new cardiovascular drugs]. | 2007 Jul-Aug |
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Ivabradine: a new strategy for management of stable angina. | 2007 Jun |
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[Heart rate as a cardiovascular risk factor: potential clinical benefit with ivabradine]. | 2007 May 30 |
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Heart rate reduction after heart transplantation with beta-blocker versus the selective If channel antagonist ivabradine. | 2007 Oct 27 |
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I f inhibition with ivabradine : electrophysiological effects and safety. | 2008 |
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Ivabradine as an alternative therapeutic trial in the therapy of inappropriate sinus tachycardia: a case report. | 2008 |
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Heart rate in the pathophysiology of coronary blood flow and myocardial ischaemia: benefit from selective bradycardic agents. | 2008 Apr |
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Effect of long-term heart rate reduction by If current inhibition on pressure overload-induced heart failure in rats. | 2008 Jan |
Patents
Sample Use Guides
The recommended starting dose of CORLANOR® is 5 mg twice daily with meals.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/16387796
The potential subtype-specificity of the sinus node inhibitors cilobradine, ivabradine, and zatebradine using cyclic nucleotide-gated cation (HCN) channels was tested. All three substances blocked the slow inward current through HCN1, HCN2, HCN3, and HCN4 human channels. There was no subtype-specificity for the steady-state block, with mean IC50 values of 0.99, 2.25, and 1.96 microM for cilobradine, ivabradine, and zatebradine, respectively.
Substance Class |
Chemical
Created
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Record UNII |
3H48L0LPZQ
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WHO-ATC |
C07FX06
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FDA ORPHAN DRUG |
511915
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NCI_THESAURUS |
C47793
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C07FX05
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QC01EB17
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631818
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C01EB17
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NDF-RT |
N0000191544
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PRIMARY | Hyperpolarization-activated Cyclic Nucleotide-gated Channel Antagonists [MoA] | ||
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PRIMARY | RxNorm |
Related Record | Type | Details | ||
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SALT/SOLVATE -> PARENT | |||
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EXCRETED UNCHANGED |
About 4% of unchanged drug was recovered either in urine or in feces, suggesting hepatic metabolism as the major route of elimination. Radioactivity associated with metabolites was excreted to a similar degree in feces (around 45%) and urine (around 37%).
FECAL; URINE
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SALT/SOLVATE -> PARENT | |||
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SALT/SOLVATE -> PARENT | |||
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TARGET -> INHIBITOR |
IC50
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SALT/SOLVATE -> PARENT | |||
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BINDER->LIGAND |
BINDING
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Related Record | Type | Details | ||
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METABOLITE ACTIVE -> PARENT |
20 mg repeated oral doses in eighteen healthy male volunteers; IVABRADINE 85 + 46 ng/mL
Cmax
PLASMA
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ACTIVE MOIETY |
Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
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Volume of Distribution | PHARMACOKINETIC |
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ORAL ADMINISTRATION |
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Tmax | PHARMACOKINETIC |
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ORAL ADMINISTRATION |
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