Cilnidipine

Identification

Summary

Cilnidipine is a dihydropyridine calcium channel blocker with action on both N- and L-type calcium channels used to treat hypertension.

Generic Name
Cilnidipine
DrugBank Accession Number
DB09232
Background

Cilnidipine is a dihydropyridine calcium antagonist. It was jointly developed by Fuji Viscera Pharmaceutical Company, Japan and Ajinomoto, Japan and approved in 1995. Compared with other calcium antagonists, cilnidipine can act on the N-type calcium channel that existing sympathetic nerve end besides acting on L-type calcium channel that similar to most of the calcium antagonists. This drug is approved in China, Japan, Korea, India, and several countries in the European Union.1

Type
Small Molecule
Groups
Investigational
Structure
Weight
Average: 492.528
Monoisotopic: 492.18965125
Chemical Formula
C27H28N2O7
Synonyms
  • Cilnidipine

Pharmacology

Indication

Cilnidipine is indicated for the management of hypertension for end-organ protection.5 It is reported to be useful in elderly patients and in those with diabetes and albuminuria. Cilnidipine has been increasingly used in patients with chronic kidney disease

Hypertension is the term used to describe the presence of high blood pressure. The blood pressure is generated by the force of the blood pumped from the heart against the blood vessels. Thus hypertension is caused when there is too much pressure on the blood vessels and this effect can damage the blood vessel.6

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofHigh blood pressure (hypertension)••••••••••••••••••• ••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Administration of cilnidipine has been shown to present an antisympathetic profile in vitro and in vivo. It decreases blood pressure safely and effectively without excessive blood pressure reduction or tachycardia.2

Mechanism of action

Cilnidipine acts on the L-type calcium channels of blood vessels by blocking the incoming calcium and suppressing the contraction of blood vessels, thereby reducing blood pressure. Cilnidipine also works on the N-type calcium channel located at the end of the sympathetic nerve, inhibiting the emission of norepinephrine and suppressing the increase in stress blood pressure.2

TargetActionsOrganism
AVoltage-dependent N-type calcium channel subunit alpha-1B
antagonist
Humans
AVoltage-dependent L-type calcium channel
antagonist
Humans
Absorption

Cilnidipine presents a very rapid absorption with a maximum peaked concentration after 2 hours. Its distribution tends to be higher in the liver as well as in kidneys, plasma and other tissues. Cilnidipine does not present a high accumulation in the tissue after repeated oral administration.8

Cilnidipine is reported to present very low bioavailability determined to be approximately 13%. This low bioavailability is suggested to be due to its low aqueous solubility and high permeability. Hence, efforts have been made in order to find an innovative formulation that can significantly improve the bioavailability of this drug. One of these formulations corresponds to the generation of polymeric nanoparticles which enhance the bioavailability by 2.5-3-fold.10

Volume of distribution

Drugs on the group of dihydropyridines such as cilnidipine tend to have a large volume of distribution.4

Protein binding

Cilnidipine presents a very high protein binding that represents to even 98% of the administered dose.8

Metabolism

Cilnidipine is metabolized by both liver and kidney. It is rapidly metabolized by liver microsomes by a dehydrogenation process. The major enzymatic isoform involved in cilnidipine dehydrogenation of the dihydropyridine ring is CYP3A.7

Route of elimination

Cilnidipine gets eliminated through the urine in a proportion of 20% of the administered dose and 80% is eliminated by the feces.7

Half-life

The half-life of the hypotensive effect for cilnidipine is of about 20.4 min.3

Clearance

Not Available

Adverse Effects
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Toxicity

The percentage of reports of cilnidipine that express drug toxicity reported as side effects are 5.26%.9

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
AbaloparatideThe risk or severity of adverse effects can be increased when Abaloparatide is combined with Cilnidipine.
AbametapirThe serum concentration of Cilnidipine can be increased when it is combined with Abametapir.
AcarboseThe risk or severity of hypoglycemia can be increased when Cilnidipine is combined with Acarbose.
AcebutololAcebutolol may increase the arrhythmogenic activities of Cilnidipine.
AceclofenacThe risk or severity of hyperkalemia can be increased when Aceclofenac is combined with Cilnidipine.
Food Interactions
Not Available

Products

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International/Other Brands
Atelec (Ajinomoto Pharmaceuticals Co. Ltd) / Cilogard (Cipla Ltd)

Categories

ATC Codes
C08CA14 — Cilnidipine
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 / Styrenes / Nitroaromatic compounds / Dicarboxylic acids and derivatives / Vinylogous amides / Enoate esters / Amino acids and derivatives / Propargyl-type 1,3-dipolar organic compounds / Azacyclic compounds / Dialkyl ethers
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Substituents
Allyl-type 1,3-dipolar organic compound / Alpha,beta-unsaturated carboxylic ester / Amine / Amino acid or derivatives / Aromatic heteromonocyclic compound / Azacycle / Benzenoid / C-nitro compound / Carbonyl group / Carboxylic acid derivative
show 26 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
dihydropyridine (CHEBI:31399)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
97T5AZ1JIP
CAS number
132203-70-4
InChI Key
KJEBULYHNRNJTE-DHZHZOJOSA-N
InChI
InChI=1S/C27H28N2O7/c1-18-23(26(30)35-14-8-11-20-9-5-4-6-10-20)25(21-12-7-13-22(17-21)29(32)33)24(19(2)28-18)27(31)36-16-15-34-3/h4-13,17,25,28H,14-16H2,1-3H3/b11-8+
IUPAC Name
3-(2-methoxyethyl) 5-(2E)-3-phenylprop-2-en-1-yl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
SMILES
COCCOC(=O)C1=C(C)NC(C)=C(C1C1=CC=CC(=C1)[N+]([O-])=O)C(=O)OC\C=C\C1=CC=CC=C1

References

General References
  1. Yoshimoto R, Dohmoto H, Yamada K, Goto A: Prolonged inhibition of vascular contraction and calcium influx by the novel 1,4-dihydropyridine calcium antagonist cinaldipine (FRC-8653). Jpn J Pharmacol. 1991 Jun;56(2):225-9. [Article]
  2. Lee J, Lee H, Jang K, Lim KS, Shin D, Yu KS: Evaluation of the pharmacokinetic and pharmacodynamic drug interactions between cilnidipine and valsartan, in healthy volunteers. Drug Des Devel Ther. 2014 Oct 8;8:1781-8. doi: 10.2147/DDDT.S68574. eCollection 2014. [Article]
  3. Uneyama H, Uchida H, Konda T, Yoshimoto R, Akaike N: Selectivity of dihydropyridines for cardiac L-type and sympathetic N-type Ca2+ channels. Eur J Pharmacol. 1999 May 28;373(1):93-100. [Article]
  4. Henrich W. (2012). Principles and practice of dialysis. Lippincott, Williams & Wilkins.
  5. Centapres monograph [Link]
  6. Hypertension Canada [Link]
  7. Kerala medical journal [Link]
  8. Lloyd healthcare [Link]
  9. Medfacts [Link]
  10. ResearchGate article [Link]
KEGG Drug
D01173
PubChem Compound
5282138
PubChem Substance
310265136
ChemSpider
4445338
BindingDB
50101813
ChEBI
31399
ChEMBL
CHEMBL452076
Wikipedia
Cilnidipine
MSDS
Download (52.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentHypertension / Syndrome, Metabolic1
4Unknown StatusTreatmentAutosomal Dominant Polycystic Kidney Disease (ADPKD)1
3CompletedTreatmentHypertension1
3CompletedTreatmentHypertension / Stroke1
2Unknown StatusTreatmentAutosomal Dominant Polycystic Kidney Disease (ADPKD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coated10 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)110ºC'MSDS'
boiling point (°C)653ºC'MSDS'
water solubilityInsoluble'MSDS'
logP4.70'MSDS'
pKa11.39'MSDS'
Predicted Properties
PropertyValueSource
Water Solubility0.000566 mg/mLALOGPS
logP4.39ALOGPS
logP4.1Chemaxon
logS-5.9ALOGPS
pKa (Strongest Acidic)19.46Chemaxon
pKa (Strongest Basic)-4.1Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area117 Å2Chemaxon
Rotatable Bond Count12Chemaxon
Refractivity137.14 m3·mol-1Chemaxon
Polarizability51.97 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
MS/MS Spectrum - , positiveLC-MS/MSsplash10-014i-0012490000-56c247612ff7c5dfa146
MS/MS Spectrum - , positiveLC-MS/MSsplash10-014i-2915100000-4bb1d47549a538dcee61
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]-215.4611
predicted
DeepCCS 1.0 (2019)
[M+H]+217.35649
predicted
DeepCCS 1.0 (2019)
[M+Na]+224.53725
predicted
DeepCCS 1.0 (2019)

Targets

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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
CACNA1B
Uniprot ID
Q00975
Uniprot Name
Voltage-dependent N-type calcium channel subunit alpha-1B
Molecular Weight
262493.84 Da
References
  1. Lee J, Lee H, Jang K, Lim KS, Shin D, Yu KS: Evaluation of the pharmacokinetic and pharmacodynamic drug interactions between cilnidipine and valsartan, in healthy volunteers. Drug Des Devel Ther. 2014 Oct 8;8:1781-8. doi: 10.2147/DDDT.S68574. eCollection 2014. [Article]
Kind
Protein group
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...

Components:
References
  1. Lee J, Lee H, Jang K, Lim KS, Shin D, Yu KS: Evaluation of the pharmacokinetic and pharmacodynamic drug interactions between cilnidipine and valsartan, in healthy volunteers. Drug Des Devel Ther. 2014 Oct 8;8:1781-8. doi: 10.2147/DDDT.S68574. eCollection 2014. [Article]

Enzymes

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. Uesawa Y, Takeuchi T, Mohri K: Integrated analysis on the physicochemical properties of dihydropyridine calcium channel blockers in grapefruit juice interactions. Curr Pharm Biotechnol. 2012 Jul;13(9):1705-17. [Article]
  2. Liu XQ, Zhao Y, Li D, Qian ZY, Wang GJ: Metabolism and metabolic inhibition of cilnidipine in human liver microsomes. Acta Pharmacol Sin. 2003 Mar;24(3):263-8. [Article]

Drug created at October 23, 2015 16:20 / Updated at May 05, 2021 20:31