Adrenergic Receptor
I(f) channel (hyperpolarization-activated cyclic nucleotide-gated channel, HCN) (IC50 = 2.2 μM for I(f) current inhibition) [4]

In vitro activity: Ivabradine HCl (also referred to as S 16257-2), a new If inhibitor with an IC 50 of 2.9 μM that selectively inhibits the sinoatrial node's pacemaker activity, is a pure heart rate reducer. A novel medication called ivabradine is used to treat stable angina pectoris symptomatically. Ivabradine works by selectively inhibiting the funny channel to lower heart rate; this is not the same mechanism as beta blockers or calcium channel blockers, two commonly prescribed antianginal medications.

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Incubation of mouse sinoatrial node cells with Ivabradine HCl (Procoralan) (1-10 μM) dose-dependently inhibited I(f) current, reducing the current amplitude by 68% at 10 μM without affecting other cardiac ion channels (e.g., ICa,L, IK) [4]
- Treatment of primary mouse cortical neurons with Ivabradine HCl (Procoralan) (10 μM) reduced glutamate-induced neuronal death by 45% and decreased reactive oxygen species (ROS) production by 38%, as detected by MTT assay and ROS-specific fluorescence staining [3]
- Ivabradine HCl (Procoralan) (5-20 μM) inhibited pentylenetetrazole (PTZ)-induced calcium influx in mouse hippocampal slices by 52% at 20 μM, contributing to its anticonvulsant activity [3]

Ivabradine hydrochloride (1, 10, 20 mg/kg; i.p.) exhibits anticonvulsant and neuroprotective properties in mice[3]. Ivabradine hydrochloride (5, 10, 20 mg/kg;p.o.; daily for 1 weeks) reduces heart rate in mice with increased sympathoadrenergic activity[4].

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In patients with chronic stable angina, oral administration of Ivabradine HCl (Procoralan) (5 mg twice daily) for 12 weeks reduced resting heart rate by 15 beats per minute (bpm) and exercise-induced heart rate by 22 bpm, with exercise tolerance improved by 18% (measured via treadmill test) compared to atenolol (50 mg once daily) [1]
- Mice with enhanced sympathoadrenergic activity (induced by chronic isoproterenol administration) received Ivabradine HCl (Procoralan) (10 mg/kg/day, po) for 7 days, resulting in a 20 bpm reduction in resting heart rate and a 30% decrease in myocardial oxygen consumption [4]
- Intraperitoneal injection of Ivabradine HCl (Procoralan) (20 mg/kg) to mice 30 minutes before PTZ administration increased the latency to convulsions by 65% and reduced convulsion severity score by 40% [3]
- In a mouse model of myocardial dysfunction, chronic administration of Ivabradine HCl (Procoralan) (5 mg/kg/day, po) for 4 weeks improved left ventricular ejection fraction by 12% and reduced myocardial fibrosis by 25% [2]

I(f) current recording assay: Mouse sinoatrial node cells were isolated and enzymatically dispersed. Cells were superfused with Tyrode's solution containing Ivabradine HCl (Procoralan) (0.1-100 μM) at 37°C. I(f) current was recorded using whole-cell patch-clamp technique with a holding potential of -40 mV and step depolarizations to -120 mV. IC50 values were calculated from dose-response curves of current inhibition [4]
- Calcium influx assay: Mouse hippocampal slices (400 μm) were preincubated with Ivabradine HCl (Procoralan) (5-20 μM) for 30 minutes, then exposed to PTZ (100 μM). Intracellular calcium concentration was measured using a calcium-sensitive fluorescent dye, and the percentage inhibition of calcium influx was quantified [3]

Glutamate-induced neuronal injury assay: Primary mouse cortical neurons were seeded in 96-well plates and cultured for 7 days. Cells were pretreated with Ivabradine HCl (Procoralan) (1-20 μM) for 1 hour, then exposed to glutamate (100 μM) for 24 hours. Cell viability was assessed by MTT assay, and ROS production was detected by incubating cells with ROS-specific fluorescent probe for 30 minutes before fluorescence intensity measurement [3]
- Cardiomyocyte protection assay: Neonatal rat cardiomyocytes were cultured in 6-well plates and treated with Ivabradine HCl (Procoralan) (5 μM) for 24 hours, then exposed to isoproterenol (1 μM) for 48 hours. Myocardial fibrosis markers (collagen I, collagen III) mRNA expression was detected by RT-PCR, showing reduced expression by 30% compared to control [2]

25-30 g, 6 weeks male Swiss mice
1, 10, 20 mg/kg
I.p.; for 3 days

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Chronic stable angina patients (n=366) were randomized to receive Ivabradine HCl (Procoralan) (5 mg twice daily, po) or atenolol (50 mg once daily, po) for 12 weeks. Resting and exercise-induced heart rate, exercise tolerance, and angina attack frequency were recorded every 4 weeks [1]
- Sympathoadrenergic hyperactivity mice: Male C57BL/6 mice (8 weeks old) received isoproterenol (2 mg/kg/day, sc) for 14 days to induce hyperactivity, then co-administered Ivabradine HCl (Procoralan) (10 mg/kg/day, po) dissolved in distilled water for 7 days. Heart rate was measured via tail-cuff plethysmography, and myocardial oxygen consumption was assessed by indirect calorimetry [4]
- Anticonvulsant mouse model: Male Swiss mice (6 weeks old) received intraperitoneal injection of Ivabradine HCl (Procoralan) (10-40 mg/kg) dissolved in 0.9% saline 30 minutes before PTZ (80 mg/kg, ip) administration. Convulsion latency, duration, and severity were recorded for 30 minutes [3]
- Myocardial dysfunction mice: Mice with left ventricular dysfunction (induced by coronary artery ligation) were treated with Ivabradine HCl (Procoralan) (5 mg/kg/day, po) via gavage for 4 weeks. Left ventricular ejection fraction was measured by echocardiography, and myocardial fibrosis was evaluated by Masson's trichrome staining [2]

In healthy volunteers, after oral administration of ivabradine hydrochloride (Procoralan) (5 mg), the peak plasma concentration (Cmax) reached 22 ng/mL in 1.5 hours, and the oral bioavailability was 40% [1]. The elimination half-life (t1/2) of ivabradine hydrochloride in humans is 6 hours, 70% of the administered dose is metabolized by hepatic CYP3A4, and 85% of the metabolites are excreted in urine [1]. In mice, after oral administration of ivabradine hydrochloride (Procoralan) (10 mg/kg), the Cmax reached 156 ng/mL in 1 hour, and the t1/2 was 3.2 hours. The drug was widely distributed, with the highest concentrations in the heart and brain tissues [3].

In clinical trials, ivabradine hydrochloride (Procoralan) (5-10 mg twice daily) was well tolerated with mild adverse reactions, including bradycardia (6%), headache (4%), and dizziness (3%); no serious hepatotoxicity or nephrotoxicity was reported [1]. - Ivabradine hydrochloride has a plasma protein binding rate of 70% in human plasma and 65% in mouse plasma [1]. - The acute oral LD50 of ivabradine hydrochloride in mice is >200 mg/kg [3].

[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 hydrochloride is the hydrochloride salt of ivabradine combined with an equimolar amount of hydrochloric acid. It is used to treat angina and/or heart failure patients who are intolerant to beta-blockers. It is a cardiotonic drug. It contains ivabradine (1+) ions. Ivabradine hydrochloride is the hydrochloride form of ivabradine, a highly bioavailable, orally bioavailable hyperpolarized activated cyclic nucleotide-gated (HCN) channel blocker with negative chronotropic effects. After administration, ivabradine selectively binds to the intracellular portion of the HCN channel pores, blocking HCN channels in sinoatrial node (SA) pacemaker cells. This inhibits the If (funny) pacemaker ion current, preventing the influx and intracellular accumulation of positively charged ions, reducing pacemaker activity, and slowing diastolic depolarization. This can lower heart rate, reduce myocardial oxygen consumption, and prolong the time it takes for blood to reach the myocardium without affecting myocardial contractility. HCN channels are mixed sodium-potassium channels that conduct inward If currents, playing a crucial role in regulating the firing rate of sinoatrial node pacemakers. If pacing currents, the influx of positively charged Na+-K+ ions, initiate spontaneous diastolic depolarization and regulate heart rate. Ivabradine is a benzozazepine derivative and a selectively hyperpolarized activated cyclic nucleotide-gated channel inhibitor that reduces 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 (containing the active ingredient).

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Drug Indications
Symptomatic treatment of chronic stable angina: Ivabradine is indicated for the treatment of chronic stable angina in adult patients with coronary artery disease, 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 angina is not adequately controlled with optimal doses of beta-blockers and require combination therapy with beta-blockers. Ivabradine is indicated for the treatment of patients with chronic heart failure of 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 intolerant. Ivabradine is also indicated for the treatment of chronic stable angina in adults with coronary artery disease, 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 poorly controlled with 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 must 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-blockers are contraindicated or intolerant. (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 must 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 who have not responded well to beta-blocker therapy when used in combination with beta-blockers. Treatment of chronic heart failure: Ivabradine is indicated for patients with chronic heart failure of NYHA functional 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. 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 angina is not adequately controlled by optimal beta-blocker doses. Ivabradine is indicated for the treatment of patients with NYHA class II to IV chronic heart failure 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. Ivabradine is also indicated for the treatment of chronic stable angina in adults with coronary artery disease who typically have a 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 rate is not adequately controlled with optimal doses of beta-blockers. Ivabradine is indicated for the treatment of patients with NYHA class II to IV chronic heart failure 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.
Treatment of angina, treatment of chronic heart failure, treatment of coronary artery disease
Treatment of angina, treatment of chronic heart failure, treatment of coronary artery disease
Ivabradine hydrochloride (Procoralan) is a selective I(f) channel inhibitor that slows the heart rate by reducing the pacing current of the sinoatrial node without affecting myocardial contractility or blood pressure[4]
- This drug has been clinically approved for the treatment of chronic stable angina and heart failure with reduced ejection fraction[1,2]
- In addition to its cardiovascular effects, Ivabradine hydrochloride (Procoralan) also exerts anticonvulsant effects by inhibiting neuronal calcium influx and neuroprotective effects by reducing the production of reactive oxygen species (ROS)[3]
- Ivabradine hydrochloride (Procoralan) slows the heart rate, improves the oxygen supply and demand balance of myocardial function, relieves angina symptoms, and prevents myocardial dysfunction[2]

C27H37CLN2O5

505.05

504.239

C, 64.21; H, 7.38; Cl, 7.02; N, 5.55; O, 15.84

148849-67-6

Ivabradine metabolite N-Demethyl Ivabradine hydrochloride; 1246638-08-3; Ivabradine-d6 hydrochloride; 2070009-63-9; Ivabradine; 155974-00-8; Ivabradine-d3 hydrochloride; 1217809-61-4; Ivabradine-d6; 1202000-62-1 (sulfate); 1086026-42-7 (oxalate); 1422274-66-5 (hemisulfate)

3045381

White to off-white solid powder

626.9ºC at 760mmHg

193-196?C

332.9ºC

1.24E-15mmHg at 25°C

4.049

1

6

10

35

663

1

Cl[H].O(C([H])([H])[H])C1=C(C([H])=C2C(=C1[H])[C@@]([H])(C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])C([H])([H])N1C(C([H])([H])C3=C([H])C(=C(C([H])=C3C([H])([H])C1([H])[H])OC([H])([H])[H])OC([H])([H])[H])=O)C2([H])[H])OC([H])([H])[H]

HLUKNZUABFFNQS-ZMBIFBSDSA-N

InChI=1S/C27H36N2O5.ClH/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;1H/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;hydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.95 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.95 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: 50 mg/mL (99.00 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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