Azelnidipine is a calcium antagonist. Preclinical studies have shown that it does not act on either N-type or T-type calcium channels. It is presumed to act on L-type calcium channels; however. [1]
Azelnidipine targets L-type and T-type voltage-dependent calcium channels. As a dihydropyridine calcium channel antagonist, it selectively binds to calcium channels in vascular smooth muscle cells. By inhibiting calcium influx, Azelnidipine causes vasodilation and reduces peripheral vascular resistance. Its high affinity for vascular tissues and antioxidative action contribute to its antiarteriosclerotic effects.

Azelnidipine is a newly developed long-acting calcium channel blocker with unique pharmacological features, e.g. cardiac slowing action and high affinity to vascular tissues, which distinguishes itself from other calcium channel blockers. Azelnidipine, thus, became a new generation of calcium channel blocker that can be used for the treatment of hypertensive patients with or without potential ischemic heart diseases. Because this new calcium antagonist is highly lipid soluble, it is retained in the vascular wall after clearance from the blood and continues to elicit a hypotensive effect.

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In vitro, Azelnidipine demonstrates high affinity for vascular tissues and exhibits antioxidative action. As a third-generation CCB, it has unique dual L-type and T-type calcium channel blockade properties. These characteristics contribute to its vasoselective effects and its ability to lower blood pressure without causing reflex tachycardia.

In a randomized double-blind study in 46 patients with essential hypertension, Azelnidipine 16 mg once daily for 6 weeks reduced 24-h average systolic blood pressure by 12 mmHg (from 141±7.9 to 129±8.5 mmHg) and diastolic blood pressure by 8 mmHg (from 94±6.1 to 86±8.8 mmHg). [1]
Daytime (07:00-21:30) systolic blood pressure decreased by 13 mmHg and diastolic by 8 mmHg; nighttime (22:00-06:30) systolic blood pressure decreased by 13 mmHg and diastolic by 8 mmHg. [1]
Pulse rate decreased slightly by 2 beats/min over 24-h average (from 70±9.0 to 68±8.9 beats/min). [1]
The hypotensive effect was stable over 24 h with a trough/peak ratio of 63.6%. [1]
No excessive nighttime blood pressure reduction was observed; the lowest nocturnal systolic blood pressure recorded after treatment was 109±8.1 mmHg (minimum individual value 94 mmHg). [1]
In vivo, Azelnidipine causes a slowly developed and long-lasting hypotensive effect with little reflex tachycardia in hypertensive animals. It can lower blood pressure without causing reflex tachycardia and has additional cardioprotective effects. Azelnidipine also offers renal protective effects. A single oral administration causes a prolonged antihypertensive effect.

Non-cellular binding assays for Azelnidipine typically involve measuring its affinity for L-type and T-type calcium channels. These assays use membrane preparations from tissues expressing the channels and measure the displacement of a labeled ligand. The compound's ability to inhibit calcium channel binding is assessed by determining IC50 values. Such assays are essential for characterizing its potency and selectivity.

In vitro cell-based assays for Azelnidipine are conducted using vascular smooth muscle cells to assess its effects on calcium channel activity and contractility. Cells are treated with the compound, and changes in intracellular calcium levels are measured using fluorescent calcium indicators. The compound's ability to inhibit vasoconstriction can be assessed in isolated blood vessel preparations.

In vivo animal studies for Azelnidipine are conducted in hypertensive animal models to evaluate its antihypertensive efficacy. The compound is administered orally, and blood pressure is measured using invasive or non-invasive methods. Its effects on heart rate, cardiac output, and renal function are assessed. These studies are essential for validating its in vivo efficacy.

Absorption, Distribution and Excretion
Oral azenidipine is rapidly absorbed in a dose-dependent manner. One study showed that after a single oral dose of 4 mg of 14C-labeled azenidipine in humans, approximately 26% of the drug was excreted in the urine and 63% in the feces within one week. A Chinese study investigated the pharmacokinetics of this drug and found its volume of distribution to be 1749 ± 964. Metabolism/Metabolites Like most drugs in its class, azenidipine is primarily metabolized via first-pass metabolism in the liver. Azenidipine is metabolized by hepatic cytochrome P450 (CYP) 3A4, with no active metabolites. It may interact with other drugs or substrates of this enzyme. Azenidipine is lipophilic and has a strong affinity for vascular smooth muscle cell membranes. Biological Half-Life 16–28 hours.

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After 6 weeks of once-daily oral administration of Azelnidipine 16 mg, plasma pharmacokinetic parameters were: Tmax = 4.14 ± 1.46 h; Cmax = 48.3 ± 19.0 ng/ml; AUC0-24 = 426 ± 151 ng·h/ml; apparent total body clearance (Cl/F) = 42,200 ± 15,400 ml/h; plasma half-life (t1/2) = 8.68 ± 1.33 h. [1]
The drug peaked at 4 h post-dose and was almost completely eliminated from blood within 24 h, showing no accumulation. [1]
Azelnidipine is highly lipophilic and retained in the vascular wall, contributing to its sustained hypotensive effect despite its short plasma half-life. [1]
Azelnidipine is an orally active compound with a molecular weight of 582.69 g/mol. It is well-absorbed from the gastrointestinal tract and has a long duration of action, allowing for once-daily dosing. Its pharmacokinetic properties have been studied in clinical settings. It is a prescription drug for the treatment of hypertension.

Protein Binding
Azenidipine binds extensively to human plasma proteins (90%–91%).

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In the Azelnidipine group (n=22), one patient suffered from soft stools (mild). [1]
Laboratory test showed a mild increase in total cholesterol. [1]
No adverse events related to excessive decrease of blood pressure were recognized. [1]
All adverse events were mild. [1]
Azelnidipine has an established safety profile from its clinical use. It has fewer adverse effects such as hot flushes and reflex tachycardia compared to other dihydropyridine CCBs. Common side effects include headache, dizziness, and peripheral edema. Comprehensive toxicological data are available from its clinical use. Azelnidipine is an approved drug in several countries.

Hypertens Res.2003 Mar;26(3):201-8;Int J Pharm.2008 Mar 3;351(1-2):55-60.

Azenidipine is an isopropyl ester. Azenidipine is a dihydropyridine calcium channel blocker. It is marketed by Daiichi Sankyo Pharmaceutical Co., Ltd. of Japan. Unlike some other calcium channel blockers, azenidipine has a slow onset of action, provides sustained blood pressure reduction, and only slightly increases heart rate. Its application in the treatment of ischemic stroke is currently under investigation. Indications: For the treatment of hypertension. Mechanism of Action: Azenidipine inhibits transmembrane Ca2+ influx through voltage-dependent channels in the vascular smooth muscle. Ca2+ channels are classified into several types, including L-type, T-type, N-type, P/Q-type, and R-type Ca2+ channels. L-type Ca2+ channels. Under normal circumstances, calcium ions induce smooth muscle contraction, leading to hypertension. When calcium channels are blocked, vascular smooth muscle cannot contract, resulting in relaxation of the vascular smooth muscle wall and a decrease in blood pressure.

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Pharmacodynamics
Azenidipine is a vasodilator that gradually lowers blood pressure in hypertensive patients. Unlike other drugs in its class, azenidipine does not induce reflex tachycardia due to vasodilation. This is likely due to its gradual blood pressure reduction. Azenidipine also has a sustained antihypertensive effect and, due to its high affinity for vascular tissue and antioxidant activity, has been shown to have a potent anti-atherosclerotic effect. Clinical studies have shown that azenidipine significantly reduces heart rate and proteinuria in hypertensive patients by inhibiting sympathetic nerve activity. Azenidipine has also been shown to have cardioprotective, neuroprotective, and anti-atherosclerotic effects, and has also been found to prevent insulin resistance.

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Background: Calcium antagonists are commonly used to treat hypertension and are particularly effective in preventing stroke. Azelnidipine is a new calcium antagonist with a pharmacokinetic profile different from amlodipine. [1]
Mechanism: Azelnidipine does not increase pulse rate but slightly decreases it (by 2 beats/min on 24-h average), suggesting no reflex sympathetic stimulation; this may avoid the disadvantages of conventional calcium antagonists on the heart. [1]
The stable 24-h hypotensive effect of Azelnidipine is attributed to its retention in the vascular wall due to high lipophilicity, as shown in preclinical studies where it could not be removed from blood vessels even by washing. [1]
Azelnidipine (Calblock) is a third-generation dihydropyridine calcium channel blocker characterized by high vascular selectivity, long duration of action, and unique dual L-type and T-type calcium channel blockade. It provides effective and sustained antihypertensive action without inducing reflex tachycardia. Azelnidipine is an approved drug for the treatment of hypertension in Japan and India.

C33H34N4O6

582.65

582.247

123524-52-7

Azelnidipine-d7

65948

Light yellow to yellow solid powder

1.3±0.1 g/cm3

709.3±60.0 °C at 760 mmHg

120-126ºC

382.8±32.9 °C

0.0±2.3 mmHg at 25°C

1.659

4.21

2

9

10

43

1080

0

ZKFQEACEUNWPMT-UHFFFAOYSA-N

InChI=1S/C33H34N4O6/c1-20(2)42-32(38)27-21(3)35-31(34)29(28(27)24-15-10-16-25(17-24)37(40)41)33(39)43-26-18-36(19-26)30(22-11-6-4-7-12-22)23-13-8-5-9-14-23/h4-17,20,26,28,30,35H,18-19,34H2,1-3H3

3-(1-benzhydrylazetidin-3-yl) 5-isopropyl 2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

UR-12592; UR-12592; UR-12592; CS 905; CS-905; CS905; CCRIS 8650; CCRIS8650; CCRIS-8650; Azelnidipine; trade name CalBlock.

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.29 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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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 (Please use freshly prepared in vivo formulations for optimal results.)