Azelnidipine

Identification

Generic Name

Azelnidipine

DrugBank Accession Number

DB09230

Background

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 ³. It is currently being studied for post-ischemic stroke management ⁴.

Type

Small Molecule

Groups

Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Azelnidipine (DB09230)

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Weight

Average: 582.657
Monoisotopic: 582.247834831

Chemical Formula

C₃₃H₃₄N₄O₆

Synonyms

• Azelnidipine

External IDs

• CS-905

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Pharmacology

Indication

For the treatment of hypertension.

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Contraindications & Blackbox Warnings

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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 ².

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 ².

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 ⁶. 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.

Target	Actions	Organism
UVoltage-dependent L-type calcium channel subunit beta-1	agonist	Humans

Absorption

Oral ingestion of azelnidipine demonstrates rapid and dose-dependent absorption ⁶.

Volume of distribution

In a Chinese study examining the pharmacokinetics of the drug, the volume of distribution was found to be 1749 +/- 964 ⁷.

Protein binding

Azelnidipine is widely bound to human plasma proteins (90%–91%) ⁷.

Metabolism

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 ⁶.

Route of elimination

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 ².

Half-life

16 –28 hours ⁷.

Clearance

Not Available

Adverse Effects

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Toxicity

As with any calcium channel blocker toxicity, bradycardia and hypotension may result from overdose. The treatment of patients with bradycardia and hypotension begins with supportive therapy and atropine, however, patients with severe toxicity do not have an adequate response and must be managed more aggressively.

Calcium plays an imperative role in myocardial contractility, automaticity and vascular tone. Administration of exogenous calcium is of benefit in cases of toxicity ⁸.

Pathways

Not Available

Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">

Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	The serum concentration of Azelnidipine can be increased when it is combined with Abametapir.
Acarbose	The risk or severity of hypoglycemia can be increased when Azelnidipine is combined with Acarbose.
Acebutolol	Acebutolol may increase the arrhythmogenic activities of Azelnidipine.
Aceclofenac	The risk or severity of hyperkalemia can be increased when Aceclofenac is combined with Azelnidipine.
Acemetacin	The risk or severity of hyperkalemia can be increased when Azelnidipine is combined with Acemetacin.

Food Interactions

Not Available

Products

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International/Other Brands

Azelnidipine Chemipha / Azelnidipine FFP / Azelnidipine JG / Azelnidipine KOG / Azelnidipine Nichi-Iko / Azelnidipine Tanabe / Azelnidipine TCK / Azelnidipine Teva / Azelnidipine Towa / Azelnidipine YD / Beiqi / Calblock / Rezaldas HD / Rezaltas LD

Categories

Drug Categories

• Acids, Acyclic
• Agents causing hyperkalemia
• Amino Acids
• Amino Acids, Cyclic
• Amino Acids, Peptides, and Proteins
• Antiarrhythmic agents
• Azetidines
• Azetines
• Bradycardia-Causing Agents
• Calcium Channel Blockers
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Substrates
• Imines
• Imino Acids
• Pyridines
• Vasodilating Agents

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.

Kingdom

Organic compounds

Super Class

Benzenoids

Class

Benzene and substituted derivatives

Sub Class

Diphenylmethanes

Direct Parent

Diphenylmethanes

Alternative Parents

Dihydropyridinecarboxylic acids and derivatives / Nitrobenzenes / Nitroaromatic compounds / Aralkylamines / Dicarboxylic acids and derivatives / Vinylogous amides / Enoate esters / Trialkylamines / Amino acids and derivatives / Azetidines / Ketene acetals / Propargyl-type 1,3-dipolar organic compounds / Azacyclic compounds / Dialkylamines / Organic oxoazanium compounds / Organopnictogen compounds / Carbonyl compounds / Organic zwitterions / Organic oxides / Monoalkylamines / Hydrocarbon derivatives

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Substituents

Allyl-type 1,3-dipolar organic compound / Alpha,beta-unsaturated carboxylic ester / Amine / Amino acid or derivatives / Aralkylamine / Aromatic heteromonocyclic compound / Azacycle / Azetidine / C-nitro compound / Carbonyl group / Carboxylic acid derivative / Carboxylic acid ester / Dicarboxylic acid or derivatives / Dihydropyridine / Dihydropyridinecarboxylic acid derivative / Diphenylmethane / Enoate ester / Hydrocarbon derivative / Hydropyridine / Ketene acetal or derivatives / Nitroaromatic compound / Nitrobenzene / Organic 1,3-dipolar compound / Organic nitro compound / Organic nitrogen compound / Organic oxide / Organic oxoazanium / Organic oxygen compound / Organic zwitterion / Organoheterocyclic compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Primary aliphatic amine / Propargyl-type 1,3-dipolar organic compound / Secondary aliphatic amine / Secondary amine / Tertiary aliphatic amine / Tertiary amine / Vinylogous amide

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Molecular Framework

Aromatic heteromonocyclic compounds

External Descriptors

Not Available

Affected organisms

Not Available

Chemical Identifiers

UNII

PV23P19YUG

CAS number

123524-52-7

InChI Key

ZKFQEACEUNWPMT-UHFFFAOYSA-N

InChI

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

IUPAC Name

3-[1-(diphenylmethyl)azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

SMILES

CC(C)OC(=O)C1=C(C)NC(N)=C(C1C1=CC=CC(=C1)[N+]([O-])=O)C(=O)OC1CN(C1)C(C1=CC=CC=C1)C1=CC=CC=C1

References

Synthesis Reference

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245158/

General References

1. Oizumi K, Nishino H, Koike H, Sada T, Miyamoto M, Kimura T: Antihypertensive effects of CS-905, a novel dihydropyridine Ca++ channel blocker. Jpn J Pharmacol. 1989 Sep;51(1):57-64. [Article]
2. Nada T, Nomura M, Koshiba K, Kawano T, Mikawa J, Ito S: Clinical study with azelnidipine in patients with essential hypertension. Antiarteriosclerotic and cardiac hypertrophy-inhibitory effects and influence on autonomic nervous activity. Arzneimittelforschung. 2007;57(11):698-704. doi: 10.1055/s-0031-1296670. [Article]
3. DRUG: Azelnidipine [Link]
4. Azelnidipine, a long-acting calcium channel blocker, could control hypertension without decreasing cerebral blood flow in post-ischemic stroke patients. A 123I-IMP SPECT follow-up study [Link]
5. Azelnidipine MSDS [Link]
6. Clinical use of azelnidipine in the treatment of hypertension in Chinese patients [Link]
7. Determination of azelnidipine by LC–ESI-MS and its application to a pharmacokinetic study in healthy Chinese volunteers [Link]
8. Calcium Channel Blocker Poisoning [Link]

External Links

KEGG Drug

D01145

PubChem Compound

65948

PubChem Substance

310265134

ChemSpider

59352

ChEBI

31247

ChEMBL

CHEMBL1275868

Wikipedia

Azelnidipine

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Completed	Prevention	Cardiovascular Disease (CVD) / Diabetes / Hypertension	1
4	Completed	Prevention	Cardiovascular Disease (CVD) / Hypertension	1
4	Completed	Prevention	Coronary Artery Atherosclerosis / Hypertension	1
4	Completed	Treatment	Hypertension	1
4	Unknown Status	Treatment	Cerebral Small Vessels Disease	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Not Available

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	193-195	[L1381]
water solubility	Insoluble in water	Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.00082 mg/mL	ALOGPS
logP	5.12	ALOGPS
logP	5.57	Chemaxon
logS	-5.8	ALOGPS
pKa (Strongest Acidic)	19.88	Chemaxon
pKa (Strongest Basic)	6	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	7	Chemaxon
Hydrogen Donor Count	2	Chemaxon
Polar Surface Area	137.03 Å2	Chemaxon
Rotatable Bond Count	11	Chemaxon
Refractivity	172.06 m3·mol-1	Chemaxon
Polarizability	60.76 Å3	Chemaxon
Number of Rings	5	Chemaxon
Bioavailability	0	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
MS/MS Spectrum - , positive	LC-MS/MS	splash10-0159-0900060000-c80c65ee0493cbc50569

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	225.75972	predicted	DeepCCS 1.0 (2019)
[M+H]+	227.5846	predicted	DeepCCS 1.0 (2019)
[M+Na]+	233.19043	predicted	DeepCCS 1.0 (2019)

Targets

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Details1. Voltage-dependent L-type calcium channel subunit beta-1

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Agonist

General Function

Voltage-gated calcium channel activity

Specific Function

The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and ina...

Gene Name

CACNB1

Uniprot ID

Q02641

Uniprot Name

Voltage-dependent L-type calcium channel subunit beta-1

Molecular Weight

65712.995 Da

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Drug created at October 23, 2015 16:13 / Updated at February 03, 2022 06:25