Identification

Name
Aranidipine
Accession Number
DB09229
Type
Small Molecule
Groups
Approved, Investigational
Description

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]

Structure
Thumb
Synonyms
Not Available
International/Other Brands
Sapresta
Categories
UNII
4Y7UR6X2PO
CAS number
86780-90-7
Weight
Average: 388.376
Monoisotopic: 388.127050992
Chemical Formula
C19H20N2O7
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

Pharmacology

Indication

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

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
Human
AVoltage-dependent L-type calcium channel subunit alpha-1D
antagonist
Human
AVoltage-dependent L-type calcium channel subunit alpha-1F
antagonist
Human
AVoltage-dependent L-type calcium channel subunit alpha-1S
antagonist
Human
UAlpha adrenergic receptor
agonist
Human
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]

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
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]

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbafunginThe therapeutic efficacy of Abafungin can be increased when used in combination with Aranidipine.
AcepromazineThe risk or severity of hypotension can be increased when Acepromazine is combined with Aranidipine.
AlbaconazoleThe therapeutic efficacy of Albaconazole can be increased when used in combination with Aranidipine.
AlclometasoneThe metabolism of Aranidipine can be decreased when combined with Alclometasone.
AlcuroniumAranidipine may increase the neuromuscular blocking activities of Alcuronium.
AlfuzosinThe risk or severity of hypotension can be increased when Alfuzosin is combined with Aranidipine.
AmcinonideThe metabolism of Aranidipine can be decreased when combined with Amcinonide.
Aminosalicylic AcidAranidipine may increase the anticoagulant activities of Aminosalicylic Acid.
AmiodaroneThe metabolism of Aranidipine can be decreased when combined with Amiodarone.
AmitriptylineThe metabolism of Amitriptyline can be decreased when combined with Aranidipine.
Food Interactions
Not Available

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. [PubMed:9007851]
  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. [PubMed:10836731]
  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. [PubMed:10493269]
  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. [PubMed:8667194]
  5. Allen R. (1988). Annual reports in medicinal chemistry (23rd ed.). Academic press.
  6. Researchgate [Link]
External Links
KEGG Drug
D01562
PubChem Compound
2225
PubChem Substance
310265133
ChemSpider
2139
ChEBI
31232
ChEMBL
CHEMBL2104030
Wikipedia
Aranidipine

Clinical Trials

Clinical Trials
Not Available

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 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

Taxonomy

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
Dihydropyridinecarboxylic acid derivative / Nitrobenzene / Nitroaromatic compound / Alpha-acyloxy ketone / Monocyclic benzene moiety / Dicarboxylic acid or derivatives / Benzenoid / Vinylogous amide / Methyl ester / Alpha,beta-unsaturated carboxylic ester
show 25 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
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]
Kind
Protein
Organism
Human
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]
Kind
Protein
Organism
Human
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]
Kind
Protein
Organism
Human
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]
Kind
Protein group
Organism
Human
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:
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. [PubMed:8667194]

Enzymes

Kind
Protein
Organism
Human
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

Kind
Protein
Organism
Human
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]
Kind
Protein
Organism
Human
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 on October 23, 2015 10:10 / Updated on August 26, 2018 02:04