In mice, ivabradine (1, 10, 20 mg/kg; i.p.) exhibits neuroprotective and anticonvulsant properties [3]. In mice with elevated sympathetic adrenergic activity, ivabradine (5, 10, 20 mg/kg; oral; once daily for 1 week) lowers heart rate [4].

Animal/Disease Models: 25-30 g, 6weeks old male Swiss mice [3]
Doses: 1, 10, 20 mg/kg
Route of Administration: intraperitoneal (ip) injection; continued for 3 days
Experimental Results: Attenuated PTZ and PICRO-induced seizures, while Antioxidant effects were present in all studied brain regions and diminished the expression of cleaved caspase-3 in the CA1 and DG regions of PICRO- and PTZ-treated mice, respectively.

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Animal/Disease Models: 3-4 month old transgenic (TG) mice with cardiac restriction overexpressing b2AR[4]
Doses: 5, 10, 20 mg/kg
Route of Administration: Oral; one time/day for 1 week
Experimental Results: diminished Maximal HR increased in response to 10 mg/kg beta agonist isoproterenol without changing contractile parameters in response.

Absorption, Distribution and Excretion
Ivabradine is recommended to be taken with food to reduce variability in systemic exposure. Taking it with food may slow absorption by 1 hour but may increase systemic absorption by 20-30%. The oral bioavailability of ivabradine is approximately 40%. Metabolites are excreted in feces and urine on average. Approximately 100 liters. Total clearance is approximately 400 ml/min; renal clearance is approximately 70 ml/min. Approximately 4% is excreted unchanged in the urine. Metabolism/Metabolites Ivabradine is primarily metabolized by oxidative metabolism in the intestine and liver via cytochrome P450 3A4 enzymes. Its active metabolite, the N-demethylated derivative, is also metabolized by CYP 3A4. Ivabradine has a low affinity for CYP 3A4 and is therefore unlikely to affect the metabolism of other drugs; however, potent CYP 3A4 inhibitors or inducers may affect the plasma concentrations and pharmacodynamic effects of ivabradine and should therefore not be used concurrently with ivabradine.

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Biological half-life
2 hours.

Hepatotoxicity
In large pre-registration clinical trials, the proportion of patients taking ivabradine and those taking placebo was similar [15% vs 17%], while ALT elevations exceeding 5 times the upper limit of normal were uncommon [Probability score: E (unlikely to be a cause of clinically significant liver injury)]. Protein binding 70% is bound to plasma proteins.

[1]. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005 Dec;26(23):2529-36.

[2]. Heart rate slowing for myocardial dysfunction/heart failure. Adv Cardiol. 2006;43:97-105.

[3]. Ivabradine possesses anticonvulsant and neuroprotective action in mice. Biomed Pharmacother. 2019 Jan;109:2499-2512.

[4]. I(f) channel inhibitor ivabradine lowers heart rate in mice with enhanced sympathoadrenergic activities. Br J Pharmacol. 2004 May;142(1):107-12.

Ivabradine belongs to the benzodiazepine class of compounds, with the chemical name 7,8-dimethoxy-1,3,4,5-tetrahydro-3-benzodiazepine-2-one, in which the amide hydrogen is replaced by the [{[(7S)-3,4-dimethoxybicyclo[4.2.0]oct-1,3,5-trien-7-yl]methyl}(methyl)amino]propyl} group. It (in hydrochloride form) is used to treat angina and/or heart failure patients intolerant to beta-blockers. It is a cardiotonic drug. It is a benzodiazepine, tertiary amine, carbon bicyclic compound, and aromatic ether. It is the conjugate base of ivabradine (1+).
Ivabradine is a novel heart rate-lowering drug used to treat stable angina and symptomatic chronic heart failure. Ivabradine (brand name: Corlanor) was approved by the FDA in April 2015 for the treatment of chronic heart failure patients with an ejection fraction ≤35%, sinus rhythm, and a resting heart rate ≥70 bpm, who are not currently taking beta-blockers or are receiving maximal doses of beta-blockers due to contraindications. Recently, ivabradine has been approved for the treatment of symptomatic heart failure in patients with dilated cardiomyopathy for 6 months or longer. Ivabradine's mechanism of action is to selectively and dose-dependently inhibit the pacemaker current (If) of the "interesting" channel in the sinoatrial node, thereby reducing heart rate and increasing myocardial blood flow. While non-dihydropyridine calcium channel blockers and beta-blockers can also effectively reduce heart rate, they can cause adverse reactions due to their negative inotropic effects. Therefore, because ivabradine is a drug that exerts a "pure" heart rate-lowering effect by selectively acting on the If channel, it is less likely to cause serious adverse reactions and may therefore have a better side effect profile. Ivabradine is a hyperpolarization-activated cyclic nucleotide (HCN)-gated channel blocker. Its mechanism of action is as a hyperpolarization-activated cyclic nucleotide (HCN)-gated channel antagonist. Ivabradine is a small molecule inhibitor of If ion channels used to reduce the heart rate in patients with symptomatic heart failure whose resting heart rate remains above 70 beats/min despite taking optimal doses of beta-blockers or who are intolerant to beta-blockers. No cases of elevated serum enzymes or clinically significant liver injury have been reported during Ivabradine treatment. Ivabradine is an orally bioavailable hyperpolarization-activated cyclic nucleotide (HCN) channel blocker with negative chronotropic effects. After administration, ivabradine selectively binds to the intracellular portion of the HCN channel pore, blocking HCN channels in sinoatrial node (SA) pacemaker cells. This inhibits If (funny) pacemaker ion currents, preventing the influx and intracellular accumulation of positively charged ions, reducing pacemaker activity, and slowing diastolic depolarization. This lowers heart rate, reduces myocardial oxygen consumption, and prolongs the time it takes for blood to reach the myocardium without affecting myocardial contractility. HCN channels are mixed sodium (Na+) and potassium (K+) channels that carry If influx currents and play a crucial role in regulating the firing rate of the sinoatrial node pacemaker. The If pacing current, the influx of positively charged Na+-K+ ions, initiates spontaneous diastolic depolarization and regulates heart rate. A benzozazepine derivative and a selectively hyperpolarized activated cyclic nucleotide-gated channel inhibitor that lowers heart rate. It is used to treat patients with chronic stable angina who cannot take beta-blockers, and to treat heart failure. See also: Ivabradine hydrochloride (active ingredient).

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Drug Indications
Ivabradine is FDA approved for the reduction of the risk of hospitalization due to worsening of heart failure in adult patients with stable symptomatic chronic heart failure who have a left ventricular ejection fraction ≤35%, sinus rhythm, resting heart rate ≥70 bpm, and are currently taking the maximum tolerated dose of a beta-blocker or have contraindications to beta-blockers. This product is also indicated for the treatment of stable symptomatic heart failure in children 6 months and older due to dilated cardiomyopathy.
FDA Label
Symptomatic Treatment of Chronic Stable Angina Ivabradine is indicated for the treatment of symptomatic chronic stable angina in adult patients with coronary artery disease who have a normal sinus rhythm and a heart rate ≥70 bpm. Ivabradine is indicated for: adult patients who cannot tolerate or have contraindications to beta-blockers; and patients whose heart failure is not adequately controlled with the optimal dose of beta-blockers. Ivabradine is indicated for the treatment of chronic heart failure with systolic dysfunction in patients with New York Heart Association (NYHA) class II to IV, who have sinus rhythm and a heart rate ≥75 bpm, in combination with standard therapy, including beta-blockers, or when beta-blockers are contraindicated or intolerable. Ivabradine is also indicated for the treatment of symptoms of chronic stable angina in adult patients with coronary artery disease and normal sinus rhythm and a heart rate ≥70 bpm. Ivabradine is indicated for: adult patients who cannot tolerate or have contraindications to beta-blockers, or in combination with beta-blockers in patients whose heart is not adequately controlled with optimal doses of beta-blockers. Treatment of chronic heart failure: Ivabradine is indicated for patients with chronic heart failure with systolic dysfunction in patients with New York Heart Association (NYHA) class II to IV, who have sinus rhythm and a heart rate ≥75 bpm, in combination with standard therapy, including beta-blockers, or when beta-blockers are contraindicated or intolerable.
Symptomatic treatment of chronic stable angina: Ivabradine is indicated for the symptomatic treatment of chronic stable angina in adult patients with coronary artery disease who have a normal sinus rhythm and a heart rate ≥70 bpm. Ivabradine is indicated for: - adult patients who cannot tolerate or have contraindications to beta-blockers; - or in combination with beta-blockers in patients whose heart rate is not adequately controlled by optimal doses of beta-blockers. Treatment of chronic heart failure: Ivabradine is indicated for patients with chronic heart failure of NYHA class II to IV with systolic dysfunction who have a sinus rhythm and a heart rate ≥75 bpm, and may be used in combination with standard therapy, including beta-blockers, or in cases where beta-blocker therapy is contraindicated or intolerable. (See Section 5.1)
Symptomatic treatment of chronic stable angina: Ivabradine is indicated for the symptomatic treatment of chronic stable angina in adult patients with coronary artery disease who have a normal sinus rhythm and a heart rate ≥70 bpm. Ivabradine is indicated for: adult patients who cannot tolerate or have contraindications to beta-blockers, or patients whose response to beta-blocker therapy is inadequate when used in combination with beta-blockers. For the treatment of chronic heart failure: Ivabradine is indicated for patients with chronic heart failure of NYHA functional class II to IV with systolic dysfunction, who have sinus rhythm and a heart rate ≥75 bpm. It can be used in combination with standard therapy, including beta-blockers, or in cases where beta-blocker therapy is contraindicated or intolerable. For the symptomatic treatment of chronic stable angina: Ivabradine is indicated for the symptomatic treatment of chronic stable angina in adult patients with coronary artery disease, who have normal sinus rhythm and a heart rate ≥70 bpm. Ivabradine is indicated for: adult patients who cannot tolerate or have contraindications to beta-blockers, or patients whose beta-blocker dose control is inadequate when used in combination with beta-blockers. Ivabradine is indicated for the treatment of patients with chronic heart failure and systolic dysfunction, NYHA class II to IV, with sinus rhythm and a heart rate ≥75 bpm, in combination with standard therapy, including beta-blockers, or when beta-blockers are contraindicated or intolerable. Ivabradine is also indicated for the treatment of chronic stable angina in adults with coronary artery disease, who typically have normal sinus rhythm and a heart rate ≥70 bpm. Indications for ivabradine include: - adult patients who cannot tolerate or have contraindications to beta-blockers; - or in combination with beta-blockers in patients whose heart failure is not adequately controlled with optimal doses of beta-blockers. Ivabradine is indicated for the treatment of patients with chronic heart failure, NYHA class II to IV, with systolic dysfunction, sinus rhythm, and a heart rate ≥75 bpm, in combination with standard therapy, including beta-blockers, or when beta-blockers are contraindicated or intolerable.

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Mechanism of Action
Ivabradine lowers heart rate by selectively inhibiting If channels (“interesting channels”) in the heart in a concentration-dependent manner, without affecting any other cardiac ion channels (including calcium or potassium channels). Ivabradine enters from the intracellular side and binds to specific sites on the channel pores, thereby blocking If ion currents, prolonging diastolic depolarization, and lowering heart rate. If currents are located in the sinoatrial node, the site of all cardiac pacing activity. Therefore, ivabradine reduces the pacemaker firing rate, thereby lowering heart rate and reducing myocardial oxygen consumption. This helps improve oxygen supply, thereby alleviating ischemia, improving exercise capacity, and reducing angina attacks.

C27H36N2O5

468.59

468.262

155974-00-8

Ivabradine hydrochloride;148849-67-6;Ivabradine-d6 hydrochloride;2070009-63-9;Ivabradine-d3 hydrochloride;1217809-61-4;Ivabradine-d6

132999

Typically exists as solid at room temperature

1.1±0.1 g/cm3

626.9±55.0 °C at 760 mmHg

332.9±31.5 °C

0.0±1.8 mmHg at 25°C

1.560

3.69

0

6

10

34

663

1

CN(CCCN1CCC2=CC(=C(C=C2CC1=O)OC)OC)C[C@H]3CC4=CC(=C(C=C43)OC)OC

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

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

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)