在小鼠中，伊伐布雷定（1、10、20 mg/kg；腹腔注射）具有神经保护和抗惊厥特性 [3]。在交感肾上腺素能活性升高的小鼠中，伊伐布雷定（5、10、20 mg/kg；口服；每天一次，持续 1 周）可降低心率 [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.

---

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
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.

---

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.

---

Biological Half-Life
2 hours.

Hepatotoxicity
In 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 [
Likelihood score: E (unlikely cause of clinically apparent liver injury).

---

Protein Binding
70% 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 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 a benzazepine, a tertiary amino compound, a carbobicyclic compound and an aromatic ether. It is a conjugate base of an ivabradine(1+).
Ivabradine is a novel heart rate lowering medicine for the symptomatic management of stable angina pectoralis and symptomatic chronic heart failure. Ivabradine, brand name Corlanor, was approved by the FDA in April 2015 for the treatment of chronic heart failure in patients with an ejection fraction of ≤35%, in sinus rhythm with resting heart rate ≥70 beats per minute, who are not on beta-blockers due to contraindications or already receiving maximum beta-blocker dose. Recently a new indication was added to treat symptomatic heart failure from dilated cardiomyopathy for patients 6 months or more in age. Ivabradine acts by selectively inhibiting the "funny" channel pacemaker current (If) in the sinoatrial node in a dose-dependent fashion, resulting in a lower heart rate and thus more blood to flow to the myocardium. Although non-dihydropyridine calcium channel blockers and beta blockers also effectively lower heart rate, they exhibit adverse events due to their negative ionotropic effects. Therefore, as ivabradine is designed as a "pure" heart rate-lowering drug by selectively acting on the If channels, it may offer a more favorable side effect profile due to its lower likelihood of causing serious adverse effects.
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 is a small molecule inhibitor of the If ion channel which is used to decrease the heart rate in patients with symptomatic heart failure who have a resting heart rate above 70 beats per minute despite optimal doses or intolerance of beta blockers. Ivabradine has not been associated with serum enzyme elevations during therapy or with instances of clinically apparent liver injury.
Ivabradine is an orally bioavailable, hyperpolarization-activated, cyclic nucleotide-gated (HCN) channel blocker, with negative chronotropic activity. Upon administration, ivabradine selectively binds to the intracellular portion of the HCN channel pore and blocks HCN channels in the pacemaker cells within the sinoatrial (SA) node. This inhibits the If (funny) pacemaker ion current, prevents the inward flow and intracellular accumulation of positively charged ions, reduces pacemaker activity and slows diastolic depolarization. This decreases heart rate, reduces myocardial oxygen demand and allows more time for blood to flow to the myocardium without affecting cardiac contractility. HCN channels, mixed sodium (Na+) and potassium (K+) channels that carry the inward If current, play a key role in the regulation of pacemaker firing rate in the SA node. The If pacemaker current, the inward flow of positively charged Na+-K+ ions, initiates the spontaneous diastolic depolarization phase and modulating heart rate.
A benzazepine derivative and selective HYPERPOLARIZATION-ACTIVATED CYCLIC NUCLEOTIDE-GATED CHANNELS inhibitor that lowers the heart rate. It is used in the treatment of CHRONIC STABLE ANGINA in patients unable to take BETA-ADRENERGIC BLOCKERS, and in the treatment of HEART FAILURE.
See also: Ivabradine Hydrochloride (active moiety of).

---

Drug Indication
Ivabradine is indicated by the FDA to reduce the risk of hospitalization for worsening heart failure in adult 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. It is also indicated for treatment of stable symptomatic heart failure as a result of dilated cardiomyopathy for pediatric patients 6 months of age or more.
FDA Label
Symptomatic treatment of chronic stable angina pectoris Ivabradine is indicated for the symptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm and heart rate ≥ 70 bpm. Ivabradine is indicated: in adults unable to tolerate or with a contra-indication to the use of beta-blockersorin combination with beta-blockers in patients inadequately controlled with an optimal beta-blocker dose. Treatment of chronic heart failure Ivabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥ 75 bpm, in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated.
Symptomatic treatment of chronic stable angina pectorisIvabradine is indicated for the symptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm and heart rate ≥ 70 bpm. Ivabradine is indicated: in adults unable to tolerate or with a contra-indication to the use of beta-blockersor in combination with beta-blockers in patients inadequately controlled with an optimal betablocker dose. Treatment of chronic heart failureIvabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥ 75 bpm, in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated.
Symptomatic treatment of chronic stable angina pectorisIvabradine is indicated for the symptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm and heart rate ≥ 70 bpm. Ivabradine is indicated : - in adults unable to tolerate or with a contra-indication to the use of beta-blockers- or in combination with beta-blockers in patients inadequately controlled with an optimal beta-blocker dose. Treatment of chronic heart failureIvabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥ 75 bpm, in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated. (see section 5. 1)
Symptomatic treatment of chronic stable angina pectorisIvabradine is indicated for the symptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm and heart rate ≥ 70 bpm. Ivabradine is indicated: in adults unable to tolerate or with a contraindication to the use of beta-blockersor in combination with beta-blockers in patients inadequately controlled with an optimal beta-blocker dose. Treatment of chronic heart failureIvabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥ 75 bpm, in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated.
Symptomatic treatment of chronic stable angina pectoris Ivabradine is indicated for the symptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm and heart rate ≥ 70 bpm. Ivabradine is indicated : in adults unable to tolerate or with a contraindication to the use of beta-blockersor in combination with beta-blockers in patients inadequately controlled with an optimal beta-blocker dose. Treatment of chronic heart failure Ivabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥ 75 bpm, in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated.
Symptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm and heart rate ≥ 70 bpm. Ivabradine is indicated: - in adults unable to tolerate or with a contra-indication to the use of beta-blockers - or in combination with beta-blockers in patients inadequately controlled with an optimal beta-blocker dose. Treatment of chronic heart failure Ivabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥ 75 bpm, in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated. ,

---

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.

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

60.47

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

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

---

注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

View More

注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

---

口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

View More

口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

---

注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

---

请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。