NAV

Aranidipine

Identification

Generic Name
Aranidipine
DrugBank Accession Number
DB09229
Background

Aranidipine is a novel dihydropyridine derivative that gives rise to two active metabolites (M-1α and M-1β) that exhibit hypotensive activity. It is a calcium antagonist with the formula methyl 2-oxopropyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate.1 It was developed by Maruko Seiyaku, introduced by Taiho and launched in Japan in 1997.5

Type
Small Molecule
Groups
Experimental
Structure
3D
Similar Structures
Weight
Average: 388.376
Monoisotopic: 388.127050992
Chemical Formula
C19H20N2O7
Synonyms
  • Aranidipine
External IDs
  • MPC 1304
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Pharmacology

Indication

Aranidipine has been used for many years to treat angina pectoris and hypertension.1

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Pre-clinical studies with aranidipine and its two metabolites have shown production of increases in femoral blood flow. It has been shown to present potent and long-lasting vasodilating actions. Aranidipine and its metabolites are shown to inhibit calcium-induced contraction in isolated rabbit arteries.1 Studies have shown that aranidipine is more potent to reduce blood pressure than other dihydropyridines.2 Aranidipine produce changes in renal blood flow, this effect may be explained by its effect on alpha-2-adrenoreceptor-mediated vasoconstriction.4

Mechanism of action

The high potential of aranidipine is thought to be related to the additional calcium antagonistic activity of its metabolite. The mechanism is thought to be related to the capacity of aranidipine and its metabolites to vasodilate afferent and efferent arterioles. this action is performed through the inhibition of voltage-dependent calcium channels.2 The typical mechanism of action of aranidipine, as all dihydropyridines, is based on the inhibition of L-type calcium channels, decreasing calcium concentration and inducing smooth muscle relaxation.3 It is a selective alpha2-adrenoreceptor antagonist which inhibits vasoconstrictive responses.5

TargetActionsOrganism
AVoltage-dependent L-type calcium channel subunit alpha-1C
antagonist
Humans
AVoltage-dependent L-type calcium channel subunit alpha-1D
antagonist
Humans
AVoltage-dependent L-type calcium channel subunit alpha-1F
antagonist
Humans
AVoltage-dependent L-type calcium channel subunit alpha-1S
antagonist
Humans
UAlpha adrenergic receptor
agonist
Humans
UVoltage-dependent T-type calcium channel subunit alpha-1H
inhibitor
Humans
Absorption

After administration, aranidipine is rapidly absorbed from the gastrointestinal tract. After absorption, the AUC and Cmax increased linearly in a dose-dependent manner, the Cmax was attained in approximate 3.8-4.8 hours for aranidipine and 4.8-6 hours for the metabolite M-1. The bioavailability of aranidipine in rat, dog, and monkey was about 48%, 41% and 3% respectively.6

Volume of distribution

Not Available

Protein binding

The binding ratio of plasma proteins of aranidipine varies from 84-95%. This ratio of the drug is similar to the unchanged form and for the M-1 metabolite. Most of the binding happens towards serum albumin and a lower amount corresponds to the alpha1-acid glycoprotein.6

Metabolism

Eight metabolites of aranidipine were found after oral administration. These metabolites were brought by a reduction of the ketone group, oxidation of dihydropyridine ring and de-esterification at the C-3 position.6

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Route of elimination

Unchanged aranidipine is found in plasma but not in the urine after 1 hour of administration. Just a small amount of drug was found in the bile. These results indicate that the excretion profile of aranidipine is mainly driven by metabolism and not by excretion. When including the metabolites, 52-56% of the original dose is disposed in the urine, 34-45% in feces and 3-4% in expired air. The excretion in the bile was 59% of the administered dose and 63% of this portion is reabsorbed.6

Half-life

The elimination half-life of aranidipine and the M-1 metabolite are 1.1-1.2 hour and 2.7-3.5 hour respectively.6

Clearance

Not Available

Adverse Effects
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Toxicity

In toxicity studies performed in mice, rats, and beagles there was a reported LD50 of 143 mg/kg, 1982 mg/kg and 4000 mg/kg respectively. In repeated dose studies, some of the reported side effects included increased urinary volume, serum lipid, urea nitrogen, liver weight, decreased urinary osmotic pressure and hypertrophy of hepatocytes. Teratogenic studies showed a slight generation of fetal visceral abnormalities. Other toxicity studies showed no effects on fetal development, reproductive ability, genotoxic, allergenic, or oncogenic potential.6

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
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.
DrugInteraction
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interactions in your software
AbametapirThe serum concentration of Aranidipine can be increased when it is combined with Abametapir.
AcarboseThe risk or severity of hypoglycemia can be increased when Aranidipine is combined with Acarbose.
AcebutololAcebutolol may increase the arrhythmogenic activities of Aranidipine.
AceclofenacThe risk or severity of hyperkalemia can be increased when Aceclofenac is combined with Aranidipine.
AcemetacinThe risk or severity of hyperkalemia can be increased when Aranidipine is combined with Acemetacin.
Food Interactions
Not Available

Products

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International/Other Brands
Sapresta

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as dihydropyridinecarboxylic acids and derivatives. These are compounds containing a dihydropyridine moiety bearing a carboxylic acid group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyridines and derivatives
Sub Class
Hydropyridines
Direct Parent
Dihydropyridinecarboxylic acids and derivatives
Alternative Parents
Nitrobenzenes / Nitroaromatic compounds / Alpha-acyloxy ketones / Dicarboxylic acids and derivatives / Vinylogous amides / Enoate esters / Methyl esters / Amino acids and derivatives / Ketones / Organic oxoazanium compounds
show 7 more
Substituents
Allyl-type 1,3-dipolar organic compound / Alpha,beta-unsaturated carboxylic ester / Alpha-acyloxy ketone / Amine / Amino acid or derivatives / Aromatic heteromonocyclic compound / Azacycle / Benzenoid / C-nitro compound / Carbonyl group
show 25 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
4Y7UR6X2PO
CAS number
86780-90-7
InChI Key
NCUCGYYHUFIYNU-UHFFFAOYSA-N
InChI
InChI=1S/C19H20N2O7/c1-10(22)9-28-19(24)16-12(3)20-11(2)15(18(23)27-4)17(16)13-7-5-6-8-14(13)21(25)26/h5-8,17,20H,9H2,1-4H3
IUPAC Name
3-methyl 5-(2-oxopropyl) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
SMILES
COC(=O)C1=C(C)NC(C)=C(C1C1=CC=CC=C1[N+]([O-])=O)C(=O)OCC(C)=O

References

General References
  1. Miyoshi K, Miyake H, Ichihara K, Kamei H, Nagasaka M: Contribution of aranidipine metabolites with slow binding kinetics to the vasodilating activity of aranidipine. Naunyn Schmiedebergs Arch Pharmacol. 1997 Jan;355(1):119-25. [Article]
  2. Nakamura A, Hayashi K, Fujiwara K, Ozawa Y, Honda M, Saruta T: Distinct action of aranidipine and its active metabolite on renal arterioles, with special reference to renal protection. J Cardiovasc Pharmacol. 2000 Jun;35(6):942-8. [Article]
  3. Dhein S, Salameh A, Berkels R, Klaus W: Dual mode of action of dihydropyridine calcium antagonists: a role for nitric oxide. Drugs. 1999 Sep;58(3):397-404. [Article]
  4. Miyoshi K, Kanda A, Nozawa Y, Nakano M, Miyake H: Regional vascular effects of MPC-1304, a novel dihydropyridine derivative, in conscious normotensive and spontaneously hypertensive rats. J Pharmacol Exp Ther. 1996 Jun;277(3):1328-36. [Article]
  5. Allen R. (1988). Annual reports in medicinal chemistry (23rd ed.). Academic press.
  6. Researchgate [Link]
KEGG Drug
D01562
PubChem Compound
2225
PubChem Substance
310265133
ChemSpider
2139
ChEBI
31232
ChEMBL
CHEMBL2104030
Wikipedia
Aranidipine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount

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)149-150ºCOhasi and Ebihara. (1996). Cardiovascular Drugs Review.
water solubilityInsolubleOhasi and Ebihara. (1996). Cardiovascular Drugs Review.
Predicted Properties
PropertyValueSource
Water Solubility0.0112 mg/mLALOGPS
logP2.71ALOGPS
logP1.62Chemaxon
logS-4.5ALOGPS
pKa (Strongest Acidic)16.8Chemaxon
pKa (Strongest Basic)-6.6Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area124.84 Å2Chemaxon
Rotatable Bond Count8Chemaxon
Refractivity100.8 m3·mol-1Chemaxon
Polarizability38.31 Å3Chemaxon
Number of Rings2Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-182.53183
predicted
DeepCCS 1.0 (2019)
[M+H]+185.79189
predicted
DeepCCS 1.0 (2019)
[M+Na]+193.6696
predicted
DeepCCS 1.0 (2019)

Targets

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Details1. Voltage-dependent L-type calcium channel subunit alpha-1C
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Voltage-gated calcium channel activity
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1C
Uniprot ID
Q13936
Uniprot Name
Voltage-dependent L-type calcium channel subunit alpha-1C
Molecular Weight
248974.1 Da
References
  1. KEGG [Link]
Details2. Voltage-dependent L-type calcium channel subunit alpha-1D
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Voltage-gated calcium channel activity involved sa node cell action potential
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1D
Uniprot ID
Q01668
Uniprot Name
Voltage-dependent L-type calcium channel subunit alpha-1D
Molecular Weight
245138.75 Da
References
  1. KEGG [Link]
Details3. Voltage-dependent L-type calcium channel subunit alpha-1F
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Voltage-gated calcium channel activity
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1F
Uniprot ID
O60840
Uniprot Name
Voltage-dependent L-type calcium channel subunit alpha-1F
Molecular Weight
220675.9 Da
References
  1. KEGG [Link]
Details4. Voltage-dependent L-type calcium channel subunit alpha-1S
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Voltage-gated calcium channel activity
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1S
Uniprot ID
Q13698
Uniprot Name
Voltage-dependent L-type calcium channel subunit alpha-1S
Molecular Weight
212348.1 Da
References
  1. KEGG [Link]
Details5. Alpha adrenergic receptor (Protein Group)
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Protein heterodimerization activity
Specific Function
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) prot...
Components:
NameUniProt ID
Alpha-1A adrenergic receptorP35348
Alpha-1B adrenergic receptorP35368
Alpha-1D adrenergic receptorP25100
Alpha-2A adrenergic receptorP08913
Alpha-2B adrenergic receptorP18089
Alpha-2C adrenergic receptorP18825
References
  1. Miyoshi K, Kanda A, Nozawa Y, Nakano M, Miyake H: Regional vascular effects of MPC-1304, a novel dihydropyridine derivative, in conscious normotensive and spontaneously hypertensive rats. J Pharmacol Exp Ther. 1996 Jun;277(3):1328-36. [Article]
Details6. Voltage-dependent T-type calcium channel subunit alpha-1H
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Scaffold protein binding
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1H
Uniprot ID
O95180
Uniprot Name
Voltage-dependent T-type calcium channel subunit alpha-1H
Molecular Weight
259160.2 Da
References
  1. Furukawa T, Nukada T, Namiki Y, Miyashita Y, Hatsuno K, Ueno Y, Yamakawa T, Isshiki T: Five different profiles of dihydropyridines in blocking T-type Ca(2+) channel subtypes (Ca(v)3.1 (alpha(1G)), Ca(v)3.2 (alpha(1H)), and Ca(v)3.3 (alpha(1I))) expressed in Xenopus oocytes. Eur J Pharmacol. 2009 Jun 24;613(1-3):100-7. doi: 10.1016/j.ejphar.2009.04.036. Epub 2009 May 3. [Article]

Enzymes

Details1. Cytochrome P450 3A4
Kind
Protein
Organism
Humans
Pharmacological action
No
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. KEGG [Link]

Carriers

Details1. Serum albumin
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Researchgate [Link]
Details2. Alpha-1-acid glycoprotein 1
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. Researchgate [Link]

Drug created at October 23, 2015 16:10 / Updated at February 21, 2021 18:52