Azelnidipine (also called UR-12592, CS 905, Calblock and CCRIS 8650), a novel dihydropyridine derivative, is a 3rd generation and long-acting L-type calcium channel blocker, and an antihypertensive drug sold in Japan by Daiichi-Sankyo pharmaceuticals, Inc. Acute administration of azelnidipine prevents a sudden drop of cardiac function after acute stress. Unlike other L-type calcium channel blockers, azelnidipine causes minimal stimulation of the sympathetic nervous system despite its significant depressor effect. Azelnidipine may have a protective role in inflammation in atherosclerosis.

Physicochemical Properties

Molecular Formula	C33H34N4O6
Molecular Weight	582.65
Exact Mass	582.247
CAS #	123524-52-7
Related CAS #	Azelnidipine-d7
PubChem CID	65948
Appearance	Light yellow to yellow solid powder
Density	1.3±0.1 g/cm3
Boiling Point	709.3±60.0 °C at 760 mmHg
Melting Point	120-126ºC
Flash Point	382.8±32.9 °C
Vapour Pressure	0.0±2.3 mmHg at 25°C
Index of Refraction	1.659
LogP	4.21
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	9
Rotatable Bond Count	10
Heavy Atom Count	43
Complexity	1080
Defined Atom Stereocenter Count	0
InChi Key	ZKFQEACEUNWPMT-UHFFFAOYSA-N
InChi Code	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
Chemical Name	3-(1-benzhydrylazetidin-3-yl) 5-isopropyl 2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
Synonyms	UR-12592; UR-12592; UR-12592; CS 905; CS-905; CS905; CCRIS 8650; CCRIS8650; CCRIS-8650; Azelnidipine; trade name CalBlock.
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vitro	In vitro activity: 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.
ln Vivo	NA
Animal Protocol	NA NA
ADME/Pharmacokinetics	Absorption, Distribution and Excretion Oral ingestion of azelnidipine demonstrates rapid and dose-dependent absorption. In one study, following a single 4mg oral dose of 14C-labeled azelnidipine in humans, about 26% of the drug was thought to br excreted in the urine and 63% in the feces during the 1 week period post administration. In a Chinese study examining the pharmacokinetics of the drug, the volume of distribution was found to be 1749 +/- 964. Metabolism / Metabolites Like most members of its class, azelnidipine primarily undergoes first-pass hepatic metabolism. Azelnidipine is metabolized by hepatic cytochrome P450 (CYP) 3A4 and has no active metabolite product. It may interact with other drugs or compounds that are substrates for this enzyme. Azelnidipine is lipophilic and has a potent affinity for membranes of vascular smooth muscle cells. Biological Half-Life 16 –28 hours.
Toxicity/Toxicokinetics	Protein Binding Azelnidipine is widely bound to human plasma proteins (90%–91%).
References	Hypertens Res.2003 Mar;26(3):201-8;Int J Pharm.2008 Mar 3;351(1-2):55-60.
Additional Infomation	Azelnidipine is an isopropyl ester. Azelnidipine is a dihydropyridine calcium channel blocker. It is marketed by Daiichi-Sankyo pharmaceuticals, Inc. in Japan. It has a gradual onset of action and produces a long-lasting decrease in blood pressure, with only a small increase in heart rate, unlike some other calcium channel blockers. It is currently being studied for post-ischemic stroke management. Drug Indication For the treatment of hypertension. Mechanism of Action Azelnidipine inhibits trans-membrane Ca2+ influx through the voltage-dependent channels of smooth muscles in vascular walls. Ca2+ channels are classified into various categories, including L-type, T-type, N-type, P/Q-type, and R-type Ca2+ channels. The L-type Ca2+ channels. Normally, calcium induces smooth muscle contraction, contributing to hypertension. When calcium channels are blocked, the vascular smooth muscle does not contract, resulting in relaxation of vascular smooth muscle walls and decreased blood pressure. Pharmacodynamics Azelnidipine is a vasodilator that induces a gradual decrease in blood pressure in hypertensive patients. Unlike other members of its drug class, azelnidipine does not induce reflex tachycardia due to vasodilation. This is likely due to the fact that it elicits a gradual fall in blood pressure It also exhibits a prolonged hypotensive effect and has been shown to have a strong anti-arteriosclerotic action in vessels due to its high affinity for vascular tissue and antioxidative activity. Clinical studies have demonstrated that azelnidipine markedly reduced heart rate and proteinuria in hypertensive patients by inhibiting sympathetic nerve activity. Azelnidipine has also been confirmed to have cardio-protective, neuroprotective, and anti-atherosclerotic properties, and has also been found to prevent insulin resistance.

Solubility Data

Solubility (In Vitro)

DMSO:117 mg/mL (200.8 mM) Water:<1 mg/mL Ethanol:7 mg/mL (12.01 mM)

Solubility (In Vivo)

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

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.7163 mL	8.5815 mL	17.1630 mL
	5 mM	0.3433 mL	1.7163 mL	3.4326 mL
	10 mM	0.1716 mL	0.8581 mL	1.7163 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.