Identification

Name
Benidipine
Accession Number
DB09231
Type
Small Molecule
Groups
Experimental
Description

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]

Structure
Thumb
Synonyms
Not Available
Product Ingredients
IngredientUNIICASInChI Key
Benidipine hydrochloride0A6746FWDL91599-74-5KILKDKRQBYMKQX-MIPPOABVSA-N
International/Other Brands
Coniel (Kyowa Hakko Kogyo)
Categories
UNII
4G9T91JS7E
CAS number
105979-17-7
Weight
Average: 505.571
Monoisotopic: 505.22128573
Chemical Formula
C28H31N3O6
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

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]

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
Human
AVoltage-dependent N-type calcium channel subunit alpha-1B
antagonist
Human
AVoltage-dependent T-type calcium channel
antagonist
Homo sapiens
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]

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
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]

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 Benidipine.
AcepromazineThe risk or severity of hypotension can be increased when Acepromazine is combined with Benidipine.
AcetazolamideThe metabolism of Benidipine can be decreased when combined with Acetazolamide.
Acetylsalicylic acidBenidipine may increase the anticoagulant activities of Acetylsalicylic acid.
AlbaconazoleThe therapeutic efficacy of Albaconazole can be increased when used in combination with Benidipine.
AlbendazoleThe metabolism of Albendazole can be decreased when combined with Benidipine.
AlclometasoneThe metabolism of Alclometasone can be decreased when combined with Benidipine.
AlcuroniumBenidipine may increase the neuromuscular blocking activities of Alcuronium.
AlfentanilThe metabolism of Alfentanil can be decreased when combined with Benidipine.
AlfuzosinThe risk or severity of hypotension can be increased when Alfuzosin is combined with Benidipine.
Food Interactions
Not Available

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. [PubMed:3427272]
  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. [PubMed:16565579]
  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. [PubMed:17537876]
  4. IJBCP [Link]
  5. Springer [Link]
External Links
PubChem Compound
656668
PubChem Substance
310265135
ChemSpider
571013
ChEMBL
CHEMBL2105555
Wikipedia
Benidipine
ATC Codes
C08CA15 — Benidipine
MSDS
Download (291 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Not Yet RecruitingTreatmentChronic Kidney Disease (CKD)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)>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
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 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
N-benzylpiperidine / Nitrobenzene / Dihydropyridinecarboxylic acid derivative / Phenylmethylamine / Nitroaromatic compound / Benzylamine / Dihydropyridine / Aralkylamine / Monocyclic benzene moiety / Benzenoid
show 32 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

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. 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. [PubMed:16565579]
  2. IJBCP [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
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. [PubMed:16565579]
  2. IJBCP [Link]
Kind
Protein group
Organism
Homo sapiens
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. [PubMed:16565579]
  2. IJBCP [Link]

Enzymes

Kind
Protein
Organism
Human
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. [PubMed:16565579]
  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. [PubMed:17537876]
  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. [PubMed:10805063]
Kind
Protein
Organism
Human
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. [PubMed:16565579]
  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. [PubMed:17537876]

Drug created on October 23, 2015 10:16 / Updated on October 01, 2018 16:36