Benidipine

Identification

Summary

Benidipine is a synthetic dihydropyridine calcium channel blocker used to treat hypertension and angina pectoris.

Generic Name
Benidipine
DrugBank Accession Number
DB09231
Background

Benidipine has the formula 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine-dicarboxylic acid methyl 1-(phenylmethyl)-3-piperidinyl ester hydrochloride. It is a synthetic dihydropyridine derivative that has anti-hypertensive and anti-anginal actions.1 It was originated in Japan by Kyowa Hakko, it is submitted for FDA approval and it is currently available in some Asian countries like India and Japan.4,5

Type
Small Molecule
Groups
Experimental
Structure
Weight
Average: 505.571
Monoisotopic: 505.22128573
Chemical Formula
C28H31N3O6
Synonyms
  • Benidipine

Pharmacology

Indication

Benidipine is a potent and long-lasting drug indicated for the treatment of cardiovascular diseases such as hypertension, renoparenchymal hypertension and angina pectoris.2

Reduce drug development failure rates
Build, train, & validate machine-learning models
with evidence-based and structured datasets.
See how
Build, train, & validate predictive machine-learning models with structured datasets.
See how
Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofAngina pectoris••••••••••••••••••
Treatment ofAngina pectoris••••••••••••••••••• •••• ••••••
Management ofHigh blood pressure (hypertension)••••••••••••••••••
Treatment ofHigh blood pressure (hypertension)••••••••••••••••••• •••• ••••••
Treatment ofHypertension, renal••••••••••••••••••• •••• ••••••
Contraindications & Blackbox Warnings
Prevent Adverse Drug Events Today
Tap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.
Learn more
Avoid life-threatening adverse drug events with our Clinical API
Learn more
Pharmacodynamics

Benidipine reduces systolic and diastolic blood pressure as well as to present decreases in heart rate pulse after treatment. It is reported also a decrease urinary protein excretion and serum triglycerides.4 Different studies have shown benidipine anti-oxidative activity, stimulation of NO production, suppression of adhesion molecules expression, stimulation of osteoblast differentiation, suppression of the proliferation of vascular smooth muscle cells and mesangial cells, as well as myocardial protection. The enhancement of NO production is associated with the cardioprotective and antiartheriosclerotic effects of benidipine.2

Mechanism of action

Benidipine is a tripe calcium channel inhibitor by inhibiting L, N and T type calcium channel.4 It presents a very long-lasting activity that can be explained by its high affinity for cell membranes from the DHP binding site; this characteristic indicated a long-lasting pharmacological activity of benidipine. The additional property of benidipine is the vascular selectivity towards peripheral blood vessels.2

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

Benidipine is rapidly absorbed after oral administration reaching a maximum concentration within 2 hours. The short period of time needed for maximum concentration to get reached is a particular characteristic of benidipine when compared with other calcium channel blockers. The registered maximum concentration and AUC are dose-dependent and it can go from 0.55-3.89 ng/ml and 1.04-6.7 ng.h/ml respectively when administered in a dose of 2-8 mg.2

Volume of distribution

Benidipine is highly distributed to the tissues mainly in the liver and kidneys and plasma. It does not present a high accumulation following repeated oral administrations.2

Protein binding

Benidipine is highly bound to plasma proteins and the bound form can account for even 98% of the administered dose.2

Metabolism

Benidipine is almost completely metabolized in the liver. From different reports, it is thought that benidipine is mainly metabolized by CYP3A.2 Some of the formed metabolites are N-desbenzylbenidipine and dehydrobenidipine. Analysis on the formation of metabolites has indicated that the metabolism is mainly performed by CYP3A4 and CYP3A5.3

Hover over products below to view reaction partners

Route of elimination

The percentage of urinary excretion after oral administration is of approximate 36% of the administered dose. Most of the remaining dose is excreted in feces, making bile excretion the major elimination pathway of benidipine. From the eliminated drug, none of it is expressed in the form of the unchanged drug.2

Half-life

The elimination half-life of benidipine is registered to be of approximate 1 hour.2

Clearance

Not Available

Adverse Effects
Improve decision support & research outcomes
With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!
See the data
Improve decision support & research outcomes with our structured adverse effects data.
See a data sample
Toxicity

In preclinical studies, the LD50 of benidipine ranged from 87-384 mg/kg which is more than 100 times the needed dose to achieve anti-hypertensive action. There were no significant changes in histopathological heart examination. Benidipine showed no carcinogenic, antigenicity, teratogenic or mutagenic properties.2

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
1,2-BenzodiazepineThe metabolism of 1,2-Benzodiazepine can be decreased when combined with Benidipine.
AbametapirThe serum concentration of Benidipine can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Benidipine can be increased when combined with Abatacept.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Benidipine.
AbirateroneThe metabolism of Benidipine can be decreased when combined with Abiraterone.
Food Interactions
Not Available

Products

Drug product information from 10+ global regions
Our datasets provide approved product information including:
dosage, form, labeller, route of administration, and marketing period.
Access now
Access drug product information from over 10 global regions.
Access now
Product Ingredients
IngredientUNIICASInChI Key
Benidipine hydrochloride0A6746FWDL91599-74-5KILKDKRQBYMKQX-MIPPOABVSA-N
International/Other Brands
Coniel (Kyowa Hakko Kogyo)

Categories

ATC Codes
C08CA15 — Benidipine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as n-benzylpiperidines. These are heterocyclic Compounds containing a piperidine ring conjugated to a benzyl group through one nitrogen ring atom.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Piperidines
Sub Class
Benzylpiperidines
Direct Parent
N-benzylpiperidines
Alternative Parents
Dihydropyridinecarboxylic acids and derivatives / Nitrobenzenes / Phenylmethylamines / Benzylamines / Nitroaromatic compounds / Aralkylamines / Dicarboxylic acids and derivatives / Vinylogous amides / Methyl esters / Enoate esters
show 12 more
Substituents
Allyl-type 1,3-dipolar organic compound / Alpha,beta-unsaturated carboxylic ester / Amine / Amino acid or derivatives / Aralkylamine / Aromatic heteromonocyclic compound / Azacycle / Benzenoid / Benzylamine / C-nitro compound
show 32 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
4G9T91JS7E
CAS number
105979-17-7
InChI Key
QZVNQOLPLYWLHQ-ZEQKJWHPSA-N
InChI
InChI=1S/C28H31N3O6/c1-18-24(27(32)36-3)26(21-11-7-12-22(15-21)31(34)35)25(19(2)29-18)28(33)37-23-13-8-14-30(17-23)16-20-9-5-4-6-10-20/h4-7,9-12,15,23,26,29H,8,13-14,16-17H2,1-3H3/t23-,26-/m1/s1
IUPAC Name
3-(3R)-1-benzylpiperidin-3-yl 5-methyl (4R)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
SMILES
COC(=O)C1=C(C)NC(C)=C([C@@H]1C1=CC=CC(=C1)[N+]([O-])=O)C(=O)O[C@@H]1CCCN(CC2=CC=CC=C2)C1

References

General References
  1. Terada K, Nakao K, Okabe K, Kitamura K, Kuriyama H: Action of the 1,4-dihydropyridine derivative, KW-3049, on the smooth muscle membrane of the rabbit mesenteric artery. Br J Pharmacol. 1987 Nov;92(3):615-25. [Article]
  2. Yao K, Nagashima K, Miki H: Pharmacological, pharmacokinetic, and clinical properties of benidipine hydrochloride, a novel, long-acting calcium channel blocker. J Pharmacol Sci. 2006 Apr;100(4):243-61. Epub 2006 Mar 25. [Article]
  3. Yoon YJ, Kim KB, Kim H, Seo KA, Kim HS, Cha IJ, Kim EY, Liu KH, Shin JG: Characterization of benidipine and its enantiomers' metabolism by human liver cytochrome P450 enzymes. Drug Metab Dispos. 2007 Sep;35(9):1518-24. doi: 10.1124/dmd.106.013607. Epub 2007 May 30. [Article]
  4. IJBCP [Link]
  5. Springer [Link]
PubChem Compound
656668
PubChem Substance
310265135
ChemSpider
571013
ChEMBL
CHEMBL2105555
ZINC
ZINC000100014880
Wikipedia
Benidipine
MSDS
Download (291 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedPreventionCardiovascular Disease (CVD)1
4Unknown StatusTreatmentChronic Kidney Disease (CKD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coated4 mg
Tablet, film coated8 mg
Tablet4 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)>193ºC'MSDS'
water solubility<1 mg/ml'MSDS'
logP3.79Yao K, et al. J Pharmacol Sci. (2006)
pKa7.34US 4448964
Predicted Properties
PropertyValueSource
Water Solubility0.00243 mg/mLALOGPS
logP4.28ALOGPS
logP4.02Chemaxon
logS-5.3ALOGPS
pKa (Strongest Acidic)19.47Chemaxon
pKa (Strongest Basic)7.89Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area111.01 Å2Chemaxon
Rotatable Bond Count9Chemaxon
Refractivity141 m3·mol-1Chemaxon
Polarizability53.53 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-236.8553475
predicted
DarkChem Lite v0.1.0
[M-H]-217.72905
predicted
DeepCCS 1.0 (2019)
[M+H]+237.4256475
predicted
DarkChem Lite v0.1.0
[M+H]+219.55396
predicted
DeepCCS 1.0 (2019)
[M+Na]+236.8635475
predicted
DarkChem Lite v0.1.0
[M+Na]+225.15977
predicted
DeepCCS 1.0 (2019)

Targets

Build, predict & validate machine-learning models
Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
Learn more
Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
Learn more
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. Yao K, Nagashima K, Miki H: Pharmacological, pharmacokinetic, and clinical properties of benidipine hydrochloride, a novel, long-acting calcium channel blocker. J Pharmacol Sci. 2006 Apr;100(4):243-61. Epub 2006 Mar 25. [Article]
  2. IJBCP [Link]
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. Yao K, Nagashima K, Miki H: Pharmacological, pharmacokinetic, and clinical properties of benidipine hydrochloride, a novel, long-acting calcium channel blocker. J Pharmacol Sci. 2006 Apr;100(4):243-61. Epub 2006 Mar 25. [Article]
  2. IJBCP [Link]
Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
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...

Components:
References
  1. Yao K, Nagashima K, Miki H: Pharmacological, pharmacokinetic, and clinical properties of benidipine hydrochloride, a novel, long-acting calcium channel blocker. J Pharmacol Sci. 2006 Apr;100(4):243-61. Epub 2006 Mar 25. [Article]
  2. IJBCP [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
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. Yao K, Nagashima K, Miki H: Pharmacological, pharmacokinetic, and clinical properties of benidipine hydrochloride, a novel, long-acting calcium channel blocker. J Pharmacol Sci. 2006 Apr;100(4):243-61. Epub 2006 Mar 25. [Article]
  2. Yoon YJ, Kim KB, Kim H, Seo KA, Kim HS, Cha IJ, Kim EY, Liu KH, Shin JG: Characterization of benidipine and its enantiomers' metabolism by human liver cytochrome P450 enzymes. Drug Metab Dispos. 2007 Sep;35(9):1518-24. doi: 10.1124/dmd.106.013607. Epub 2007 May 30. [Article]
  3. Katoh M, Nakajima M, Shimada N, Yamazaki H, Yokoi T: Inhibition of human cytochrome P450 enzymes by 1,4-dihydropyridine calcium antagonists: prediction of in vivo drug-drug interactions. Eur J Clin Pharmacol. 2000 Feb-Mar;55(11-12):843-52. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Oxygen binding
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 oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Yao K, Nagashima K, Miki H: Pharmacological, pharmacokinetic, and clinical properties of benidipine hydrochloride, a novel, long-acting calcium channel blocker. J Pharmacol Sci. 2006 Apr;100(4):243-61. Epub 2006 Mar 25. [Article]
  2. Yoon YJ, Kim KB, Kim H, Seo KA, Kim HS, Cha IJ, Kim EY, Liu KH, Shin JG: Characterization of benidipine and its enantiomers' metabolism by human liver cytochrome P450 enzymes. Drug Metab Dispos. 2007 Sep;35(9):1518-24. doi: 10.1124/dmd.106.013607. Epub 2007 May 30. [Article]

Drug created at October 23, 2015 16:16 / Updated at February 02, 2024 22:52