Identification

Name
Cilnidipine
Accession Number
DB09232
Type
Small Molecule
Groups
Approved, Investigational
Description

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. Cilnidipine is approved for use in Japan, China, India, Korea and some European countries.[1]

Structure
Thumb
Synonyms
Not Available
International/Other Brands
Atelec (Ajinomoto Pharmaceuticals Co. Ltd) / Cilogard (Cipla Ltd)
Categories
UNII
97T5AZ1JIP
CAS number
132203-70-4
Weight
Average: 492.528
Monoisotopic: 492.18965125
Chemical Formula
C27H28N2O7
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

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]

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
Human
AVoltage dependent L type calcium channel
antagonist
Human
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]

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
Toxicity

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

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 Cilnidipine.
AcebutololThe risk or severity of adverse effects can be increased when Cilnidipine is combined with Acebutolol.
AcepromazineThe risk or severity of hypotension can be increased when Acepromazine is combined with Cilnidipine.
AlbaconazoleThe therapeutic efficacy of Albaconazole can be increased when used in combination with Cilnidipine.
AlclometasoneThe metabolism of Cilnidipine can be decreased when combined with Alclometasone.
AlcuroniumCilnidipine may increase the neuromuscular blocking activities of Alcuronium.
AldesleukinThe risk or severity of adverse effects can be increased when Cilnidipine is combined with Aldesleukin.
AlfuzosinThe risk or severity of hypotension can be increased when Alfuzosin is combined with Cilnidipine.
AliskirenThe risk or severity of adverse effects can be increased when Cilnidipine is combined with Aliskiren.
AmcinonideThe metabolism of Cilnidipine can be decreased when combined with Amcinonide.
Food Interactions
Not Available

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. [PubMed:1881002]
  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. [PubMed:25336921]
  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. [PubMed:10408255]
  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]
External Links
KEGG Drug
D01173
PubChem Compound
5282138
PubChem Substance
310265136
ChemSpider
4445338
ChEBI
31399
ChEMBL
CHEMBL452076
Wikipedia
Cilnidipine
ATC Codes
C08CA14 — Cilnidipine
MSDS
Download (52.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHigh Blood Pressure (Hypertension)1
2Unknown StatusTreatmentAutosomal Dominant Polycystic Kidney Disease (ADPKD)1
3CompletedTreatmentHigh Blood Pressure (Hypertension) / Strokes1
4CompletedTreatmentHigh Blood Pressure (Hypertension) / Metabolic Syndromes1
4Unknown StatusTreatmentAutosomal Dominant Polycystic Kidney Disease (ADPKD)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)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
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/MSsplash10-014i-0012490000-56c247612ff7c5dfa146
MS/MS Spectrum - , positiveLC-MS/MSsplash10-014i-2915100000-4bb1d47549a538dcee61

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 / 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
show 8 more
Substituents
Dihydropyridinecarboxylic acid derivative / Nitrobenzene / Nitroaromatic compound / Styrene / Monocyclic benzene moiety / Dicarboxylic acid or derivatives / Benzenoid / Enoate ester / Alpha,beta-unsaturated carboxylic ester / Vinylogous amide
show 26 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
dihydropyridine (CHEBI:31399)

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
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. [PubMed:25336921]
Kind
Protein group
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...

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. [PubMed:25336921]

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. 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. [PubMed:22039822]
  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. [PubMed:12617777]

Drug created on October 23, 2015 10:20 / Updated on August 26, 2018 02:04