Identification

Name
Manidipine
Accession Number
DB09238
Type
Small Molecule
Groups
Approved, Investigational
Description

Manidipine (INN) is a calcium channel blocker (dihydropyridine type) that is used clinically as an antihypertensive. It is selective for vasculature and does not produce effects on the heart at clinically relevant dosages.

Structure
Thumb
Synonyms
Not Available
International/Other Brands
Caslot / Madipine / Manyper
Categories
UNII
6O4754US88
CAS number
89226-50-6
Weight
Average: 610.711
Monoisotopic: 610.27913496
Chemical Formula
C35H38N4O6
InChI Key
ANEBWFXPVPTEET-UHFFFAOYSA-N
InChI
InChI=1S/C35H38N4O6/c1-24-30(34(40)44-3)32(28-15-10-16-29(23-28)39(42)43)31(25(2)36-24)35(41)45-22-21-37-17-19-38(20-18-37)33(26-11-6-4-7-12-26)27-13-8-5-9-14-27/h4-16,23,32-33,36H,17-22H2,1-3H3
IUPAC Name
3-{2-[4-(diphenylmethyl)piperazin-1-yl]ethyl} 5-methyl 2,6-dimethyl-4-(3-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)OCCN1CCN(CC1)C(C1=CC=CC=C1)C1=CC=CC=C1

Pharmacology

Indication

For the treatment of hypertension.

Pharmacodynamics

Manidipine produces vasodilation resulting in lower blood pressure [1].

Mechanism of action

Contraction of vascular smooth muscle is stimulated by Gq coupled receptors which produce calcium release from the sarcoplasmic reticulum. This is followed by opening of voltage dependent calcium channels and an influx of calcium into the cell ultimately producing contraction. Manidipine binds to and dissociates slowly from L- and T-type voltage dependent calcium channels on smooth muscle cells, blocking the entrance of extracellular calcium into the cell and preventing this contraction [1, 2]. This produces vasodilation which decreases blood pressure. Manidipine produces renal vasodilation and an increase in natriuresis. This likely contributes to the antihypertensive effect by reducing blood volume. Manidipine is selective for the vasculature and does not produce significant effects on the heart or central nervous system at clinically relevant dosages.

TargetActionsOrganism
AVoltage dependent L type calcium channel
blocker
Human
AVoltage-dependent T-type calcium channel
blocker
Homo sapiens
Absorption

The median Tmax is 1.5 h [1]. Administration with food produces an 1.3-1.6-fold increase in Cmax but no change in Tmax. Manidipine does not accumulate significantly with multiple doses.

Volume of distribution
Not Available
Protein binding

Manidipine is 99% bound to human plasma proteins [1].

Metabolism

Manidipine is extensively metabolized by CYP enzymes to pyridine derivatives and diphenylmethane derivatives which make up 4-7% and 22-24% of the dose excreted in the urine [1].

Route of elimination

Manidipine is eliminated through extensive metabolism. 63% is eliminated in the feces and 31% in the urine as metabolites [1].

Half life

The half life of elimination has been observed to be dose dependent [1]. Doses of 5, 10, and 20 mg produced half lives of 3.94, 5.02, and 7.95 h respectively.

Clearance
Not Available
Toxicity

The most common adverse events reported in clinical trials were ankle oedema (6%), headache (3.8%), palpitation (2.7%), flushing (2.2%), dizziness (1.6%), rash (0.5%) and fatigue (0.5%) [1].

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 Manidipine.
AcebutololAcebutolol may increase the hypotensive activities of Manidipine.
AceclofenacThe therapeutic efficacy of Manidipine can be decreased when used in combination with Aceclofenac.
AcemetacinThe therapeutic efficacy of Manidipine can be decreased when used in combination with Acemetacin.
AcepromazineThe risk or severity of hypotension can be increased when Acepromazine is combined with Manidipine.
Acetylsalicylic acidThe therapeutic efficacy of Manidipine can be decreased when used in combination with Acetylsalicylic acid.
AlbaconazoleThe therapeutic efficacy of Albaconazole can be increased when used in combination with Manidipine.
AlclofenacThe therapeutic efficacy of Manidipine can be decreased when used in combination with Alclofenac.
AlclometasoneThe metabolism of Alclometasone can be decreased when combined with Manidipine.
AlcuroniumManidipine may increase the neuromuscular blocking activities of Alcuronium.
Food Interactions
Not Available

References

General References
  1. Cheer SM, McClellan K: Manidipine: a review of its use in hypertension. Drugs. 2001;61(12):1777-99. [PubMed:11693466]
  2. McKeage K, Scott LJ: Manidipine: a review of its use in the management of hypertension. Drugs. 2004;64(17):1923-40. [PubMed:15329044]
External Links
PubChem Compound
4008
PubChem Substance
347827830
ChemSpider
3868
ChEBI
135849
ChEMBL
CHEMBL1085699
Wikipedia
Manidipine
ATC Codes
C08CA11 — ManidipineC09BB12 — Delapril and manidipine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentHigh Blood Pressure (Hypertension)1
4CompletedTreatmentCardiovascular Disease (CVD) / Chronic Kidney Disease (CKD) / Hypertension,Essential / Strokes1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility<1mg/mLMSDS
Predicted Properties
PropertyValueSource
Water Solubility0.000995 mg/mLALOGPS
logP5.11ALOGPS
logP5.19ChemAxon
logS-5.8ALOGPS
pKa (Strongest Acidic)19.47ChemAxon
pKa (Strongest Basic)7.89ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area116.93 Å2ChemAxon
Rotatable Bond Count12ChemAxon
Refractivity175.13 m3·mol-1ChemAxon
Polarizability65.72 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability0ChemAxon
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

Taxonomy

Description
This compound belongs to the class of organic compounds known as diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Diphenylmethanes
Direct Parent
Diphenylmethanes
Alternative Parents
Dihydropyridinecarboxylic acids and derivatives / Nitrobenzenes / Nitroaromatic compounds / Aralkylamines / N-alkylpiperazines / Dicarboxylic acids and derivatives / Vinylogous amides / Enoate esters / Methyl esters / Amino acids and derivatives
show 11 more
Substituents
Diphenylmethane / Dihydropyridinecarboxylic acid derivative / Nitrobenzene / Nitroaromatic compound / Dihydropyridine / Aralkylamine / N-alkylpiperazine / 1,4-diazinane / Dicarboxylic acid or derivatives / Hydropyridine
show 32 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein group
Organism
Human
Pharmacological action
Yes
Actions
Blocker
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. McKeage K, Scott LJ: Manidipine: a review of its use in the management of hypertension. Drugs. 2004;64(17):1923-40. [PubMed:15329044]
Kind
Protein group
Organism
Homo sapiens
Pharmacological action
Yes
Actions
Blocker
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. McKeage K, Scott LJ: Manidipine: a review of its use in the management of hypertension. Drugs. 2004;64(17):1923-40. [PubMed:15329044]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Unknown if inhibition is clinically relevant.
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. McKeage K, Scott LJ: Manidipine: a review of its use in the management of hypertension. Drugs. 2004;64(17):1923-40. [PubMed:15329044]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Unknown if inhibition is clinically relevant.
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. McKeage K, Scott LJ: Manidipine: a review of its use in the management of hypertension. Drugs. 2004;64(17):1923-40. [PubMed:15329044]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Vitamin d 24-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 oxidizes a variety of structurally un...
Gene Name
CYP1A1
Uniprot ID
P04798
Uniprot Name
Cytochrome P450 1A1
Molecular Weight
58164.815 Da
References
  1. McKeage K, Scott LJ: Manidipine: a review of its use in the management of hypertension. Drugs. 2004;64(17):1923-40. [PubMed:15329044]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. McKeage K, Scott LJ: Manidipine: a review of its use in the management of hypertension. Drugs. 2004;64(17):1923-40. [PubMed:15329044]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. McKeage K, Scott LJ: Manidipine: a review of its use in the management of hypertension. Drugs. 2004;64(17):1923-40. [PubMed:15329044]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. McKeage K, Scott LJ: Manidipine: a review of its use in the management of hypertension. Drugs. 2004;64(17):1923-40. [PubMed:15329044]
  2. 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
Unknown
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. McKeage K, Scott LJ: Manidipine: a review of its use in the management of hypertension. Drugs. 2004;64(17):1923-40. [PubMed:15329044]

Drug created on October 23, 2015 10:51 / Updated on August 02, 2018 06:16