Identification

Name
Azelnidipine
Accession Number
DB09230
Type
Small Molecule
Groups
Investigational
Description

Azelnidipine is a dihydropyridine calcium channel blocker. It is sold in Japan by Daiichi-Sankyo pharmaceuticals, Inc. Unlike nicardipine, it has a gradual onset and has a long-lasting hypotensive effect, with minimal increase in heart rate [3]. It is currently being studied for post-ischemic stroke management [4].

Structure
Thumb
Synonyms
Not Available
External IDs
CS-905
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
UNII
PV23P19YUG
CAS number
123524-52-7
Weight
Average: 582.657
Monoisotopic: 582.247834831
Chemical Formula
C33H34N4O6
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

Pharmacology

Indication

For the treatment of hypertension.

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.

TargetActionsOrganism
UVoltage-dependent L-type calcium channel subunit beta-1
agonist
Human
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%) [L3183].

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
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].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Azelnidipine can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Azelnidipine.
2,4-thiazolidinedioneThe risk or severity of hypoglycemia can be increased when Azelnidipine is combined with 2,4-thiazolidinedione.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Azelnidipine.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Azelnidipine.
5-androstenedioneThe metabolism of Azelnidipine can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Azelnidipine can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Azelnidipine.
AbafunginThe therapeutic efficacy of Abafungin can be increased when used in combination with Azelnidipine.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Azelnidipine.
Food Interactions
Not Available

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. [PubMed:2810942]
  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. [PubMed:18193691]
  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
PhaseStatusPurposeConditionsCount
4CompletedPreventionCardiovascular Disease (CVD) / High Blood Pressure (Hypertension)1
4CompletedPreventionCoronary Artery Atherosclerosis / High Blood Pressure (Hypertension)1
4RecruitingTreatmentCerebral Small Vessels Disease1
Not AvailableCompletedTreatmentHigh Blood Pressure (Hypertension) / Obstructive Sleep Apnea (OSA)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)193-195[L1381]
water solubilityInsoluble in waterNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.00082 mg/mLALOGPS
logP5.12ALOGPS
logP5.57ChemAxon
logS-5.8ALOGPS
pKa (Strongest Acidic)19.88ChemAxon
pKa (Strongest Basic)6ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area137.03 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity172.06 m3·mol-1ChemAxon
Polarizability60.76 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0159-0900060000-c80c65ee0493cbc50569

Taxonomy

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
show 11 more
Substituents
Diphenylmethane / Nitrobenzene / Dihydropyridinecarboxylic acid derivative / Nitroaromatic compound / Dihydropyridine / Aralkylamine / Dicarboxylic acid or derivatives / Hydropyridine / Vinylogous amide / Alpha,beta-unsaturated carboxylic ester
show 30 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
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

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. DRUG: Azelnidipine [Link]

Drug created on October 23, 2015 10:13 / Updated on November 02, 2018 07:00