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Identification
Name Bepridil
Accession Number DB01244 (APRD00727)
Type small molecule
Groups approved
Description

A long-acting calcium-blocking agent with significant anti-anginal activity. The drug produces significant coronary vasodilation and modest peripheral effects. It has antihypertensive and selective anti-arrhythmia activities and acts as a calmodulin antagonist. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Bepadin
Salts Not Available
Brand names
Name Company
Vascor
Brand mixtures Not Available
Categories
  • Antihypertensive Agents
  • Vasodilator Agents
  • Antiarrhythmic Agents
  • Calcium Channel Blockers
  • Anti-Arrhythmia Agents
CAS number 64706-54-3
Weight Average: 366.5396
Monoisotopic: 366.26711372
Chemical Formula C24H34N2O
InChI Key InChIKey=UIEATEWHFDRYRU-UHFFFAOYSA-N
InChI
InChI=1S/C24H34N2O/c1-21(2)19-27-20-24(25-15-9-10-16-25)18-26(23-13-7-4-8-14-23)17-22-11-5-3-6-12-22/h3-8,11-14,21,24H,9-10,15-20H2,1-2H3
Plain Text
IUPAC Name
N-benzyl-N-[3-(2-methylpropoxy)-2-(pyrrolidin-1-yl)propyl]aniline
SMILES
CC(C)COCC(CN(CC1=CC=CC=C1)C1=CC=CC=C1)N1CCCC1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Benzene and Derivatives
  • Anilines
Substructures
  • Aliphatic and Aryl Amines
  • Pyrrolidines
  • Ethers
  • Benzene and Derivatives
  • Heterocyclic compounds
  • Aromatic compounds
  • Anilines
Pharmacology
Indication For the treatment of chronic stable angina (classic effort-associated angina).
Pharmacodynamics Bepridil is a calcium channel blocker that has well characterized anti-anginal properties and known but poorly characterized type 1 anti-arrhythmic and anti-hypertensive properties. It is not related chemically to other calcium channel blockers such as diltiazem hydrochloride, nifedipine and verapamil hydrochloride.
Mechanism of action Bepridil has inhibitory effects on both the slow calcium (L-type) and fast sodium inward currents in myocardial and vascular smooth muscle, interferes with calcium binding to calmodulin, and blocks both voltage and receptor operated calcium channels. Bepridil inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle. This has been demonstrated in isolated myocardial and vascular smooth muscle preparations in which both the slope of the calcium dose response curve and the maximum calcium-induced inotropic response were significantly reduced by bepridil. In cardiac myocytes in vitro, bepridil was shown to be tightly bound to actin. Bepridil regularly reduces heart rate and arterial pressure at rest and at a given level of exercise by dilating peripheral arterioles and reducing total peripheral resistance (afterload) against which the heart works.
Absorption Rapidly and completely absorbed after oral administration.
Volume of distribution Not Available
Protein binding 99%
Metabolism Hepatic.
Route of elimination Not Available
Half life 24-50 hours
Clearance Not Available
Toxicity There has been one experience with overdosage in which a patient inadvertently took a single dose of 1600 mg of bepridil. The patient was observed for 72 hours in intensive care, but no significant adverse experiences were noted.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Medpointe pharmaceuticals medpointe healthcare inc
  • Johnson and johnson pharmaceutical research and development llc
Packagers Not Available
Dosage forms
Form Route Strength
Tablet, film coated Oral
Prices Not Available
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
water solubility Slightly soluble Not Available
logP 5.2 Not Available
Predicted Properties
Property Value Source
water solubility 6.55e-03 g/l ALOGPS
logP 5.33 ALOGPS
logP 5.49 ChemAxon
logS -4.8 ALOGPS
pKa (strongest basic) 9.16 ChemAxon
physiological charge 1 ChemAxon
hydrogen acceptor count 3 ChemAxon
hydrogen donor count 0 ChemAxon
polar surface area 15.71 ChemAxon
rotatable bond count 10 ChemAxon
refractivity 115.12 ChemAxon
polarizability 43.5 ChemAxon
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Compound C06847 Link_out
PubChem Compound 2351 Link_out
PubChem Substance 46506353 Link_out
ChemSpider 2261 Link_out
ChEBI 3061 Link_out
ChEMBL 3061 Link_out
Therapeutic Targets Database DAP000525 Link_out
PharmGKB PA164754755 Link_out
IUPHAR 2337 Link_out
Guide to Pharmacology 2337 Link_out
HET BEP Link_out
RxList http://www.rxlist.com/cgi/generic2/bepridil.htm Link_out
Drugs.com http://www.drugs.com/mtm/bepridil.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Bepridil Link_out
ATC Codes
  • C08EA02
AHFS Codes Not Available
PDB Entries Not Available
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Amprenavir Amprenavir may increase the effect and toxicity of bepridil.
Artemether Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Astemizole Increased risk of cardiotoxicity and arrhythmias
Atazanavir Atazanavir may increase the effect and toxicity of bepridil.
Cisapride Increased risk of cardiotoxicity and arrhythmias
Fosamprenavir Amprenavir increases the effect and toxicity of bepridil
Gatifloxacin Increased risk of cardiotoxicity and arrhythmias
Grepafloxacin Increased risk of cardiotoxicity and arrhythmias
Levofloxacin Increased risk of cardiotoxicity and arrhythmias
Lumefantrine Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Moxifloxacin Increased risk of cardiotoxicity and arrhythmias
Ritonavir Ritonavir increases the effect and toxicity of bepridil
Sparfloxacin Increased risk of cardiotoxicity and arrhythmias
Telavancin Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Terfenadine Increased risk of cardiotoxicity and arrhythmias
Tipranavir Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Bepridil. Concomitant therapy is contraindicated.
Food Interactions
  • Take with food to reduce nausea.
Targets

1. Voltage-dependent P/Q-type calcium channel subunit alpha-1A

Pharmacological action: yes
Actions: inhibitor

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, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1A gives rise to P and/or Q-type calcium currents. P/Q-type calcium channels belong to the "high-voltage activated" (HVA) group and are blocked by the funnel toxin (Ftx) and by the omega-agatoxin- IVA (omega-Aga-IVA). They are however insensitive to dihydropyridines (DHP), and omega-conotoxin-GVIA (omega-CTx-GVIA)

Organism class: human
UniProt ID: O00555 Link_out
Gene: CACNA1A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Bezprozvanny I, Tsien RW: Voltage-dependent blockade of diverse types of voltage-gated Ca2+ channels expressed in Xenopus oocytes by the Ca2+ channel antagonist mibefradil (Ro 40-5967). Mol Pharmacol. 1995 Sep;48(3):540-9. Pubmed

2. Voltage-dependent T-type calcium channel subunit alpha-1H

Pharmacological action: yes
Actions: inhibitor

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, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1H gives rise to T-type calcium currents. T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by nickel and mibefradil. A particularity of this type of channels is an opening at quite negative potentials, and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes

Organism class: human
UniProt ID: O95180 Link_out
Gene: CACNA1H Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Cohen CJ, Spires S, Van Skiver D: Block of T-type Ca channels in guinea pig atrial cells by antiarrhythmic agents and Ca channel antagonists. J Gen Physiol. 1992 Oct;100(4):703-28. Pubmed
  2. Bezprozvanny I, Tsien RW: Voltage-dependent blockade of diverse types of voltage-gated Ca2+ channels expressed in Xenopus oocytes by the Ca2+ channel antagonist mibefradil (Ro 40-5967). Mol Pharmacol. 1995 Sep;48(3):540-9. Pubmed

3. Voltage-dependent calcium channel subunit alpha-2/delta-2

Pharmacological action: yes
Actions: inhibitor
Organism class: human
UniProt ID: Q9NY47 Link_out
Gene: CACNA2D2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Cohen CJ, Spires S, Van Skiver D: Block of T-type Ca channels in guinea pig atrial cells by antiarrhythmic agents and Ca channel antagonists. J Gen Physiol. 1992 Oct;100(4):703-28. Pubmed
  2. Bezprozvanny I, Tsien RW: Voltage-dependent blockade of diverse types of voltage-gated Ca2+ channels expressed in Xenopus oocytes by the Ca2+ channel antagonist mibefradil (Ro 40-5967). Mol Pharmacol. 1995 Sep;48(3):540-9. Pubmed

4. Sodium/potassium-transporting ATPase alpha-1 chain

Pharmacological action: unknown
Actions: inhibitor

This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action creates the electrochemical gradient of sodium and potassium ions, providing the energy for active transport of various nutrients

Organism class: human
UniProt ID: P05023 Link_out
Gene: ATP1A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Kovacic H, Gallice P, Crevat A: Inhibition of sodium pump by bepridil. An in vitro and microcalorimetric study. Biochem Pharmacol. 1992 Oct 20;44(8):1529-34. Pubmed
  2. Raess BU, Record DM: Inhibition of erythrocyte Ca2()-pump by Ca2 antagonists. Biochem Pharmacol. 1990 Dec 1;40(11):2549-55. Pubmed
  3. Smith SJ, England PJ: The effects of reported Ca2+ sensitisers on the rates of Ca2+ release from cardiac troponin C and the troponin-tropomyosin complex. Br J Pharmacol. 1990 Aug;100(4):779-85. Pubmed
  4. Lamers JM, Cysouw KJ, Verdouw PD: Slow calcium channel blockers and calmodulin. Effect of felodipine, nifedipine, prenylamine and bepridil on cardiac sarcolemmal calcium pumping ATPase. Biochem Pharmacol. 1985 Nov 1;34(21):3837-43. Pubmed
  5. Fuchs J, Mainka L, Reifart N, Zimmer G: Effects of bepridil on heart mitochondrial membrane and the isolated rat heart preparation. Arzneimittelforschung. 1986 Feb;36(2):209-12. Pubmed

5. Potassium voltage-gated channel subfamily KQT member 1

Pharmacological action: unknown
Actions: inhibitor

Probably important in cardiac repolarization. Associates with KCNE1 (MinK) to form the I(Ks) cardiac potassium current. Elicits a rapidly activating, potassium-selective outward current. Muscarinic agonist oxotremorine-M strongly suppresses KCNQ1/KCNE1 current in CHO cells in which cloned KCNQ1/KCNE1 channels were coexpressed with M1 muscarinic receptors. May associate also with KCNE3 (MiRP2) to form the potassium channel that is important for cyclic AMP-stimulated intestinal secretion of chloride ions, which is reduced in cystic fibrosis and pathologically stimulated in cholera and other forms of secretory diarrhea

Organism class: human
UniProt ID: P51787 Link_out
Gene: KCNQ1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chouabe C, Drici MD, Romey G, Barhanin J: Effects of calcium channel blockers on cloned cardiac K+ channels IKr and IKs. Therapie. 2000 Jan-Feb;55(1):195-202. Pubmed
  2. Yumoto Y, Horie M, Kubota T, Ninomiya T, Kobori A, Takenaka K, Takano M, Niwano S, Izumi T: Bepridil block of recombinant human cardiac IKs current shows a time-dependent unblock. J Cardiovasc Pharmacol. 2004 Feb;43(2):178-82. Pubmed
  3. Chouabe C, Drici MD, Romey G, Barhanin J, Lazdunski M: HERG and KvLQT1/IsK, the cardiac K+ channels involved in long QT syndromes, are targets for calcium channel blockers. Mol Pharmacol. 1998 Oct;54(4):695-703. Pubmed

6. Troponin C, slow skeletal and cardiac muscles

Pharmacological action: unknown
Actions: other

Troponin is the central regulatory protein of striated muscle contraction. Tn consists of three components:Tn-I which is the inhibitor of actomyosin ATPase, Tn-T which contains the binding site for tropomyosin and Tn-C. The binding of calcium to Tn-C abolishes the inhibitory action of Tn on actin filaments

Organism class: human
UniProt ID: P63316 Link_out
Gene: TNNC1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Abusamhadneh E, Abbott MB, Dvoretsky A, Finley N, Sasi S, Rosevear PR: Interaction of bepridil with the cardiac troponin C/troponin I complex. FEBS Lett. 2001 Sep 28;506(1):51-4. Pubmed
  2. Wang X, Li MX, Sykes BD: Structure of the regulatory N-domain of human cardiac troponin C in complex with human cardiac troponin I147-163 and bepridil. J Biol Chem. 2002 Aug 23;277(34):31124-33. Epub 2002 Jun 11. Pubmed
  3. MacLachlan LK, Reid DG, Mitchell RC, Salter CJ, Smith SJ: Binding of a calcium sensitizer, bepridil, to cardiac troponin C. A fluorescence stopped-flow kinetic, circular dichroism, and proton nuclear magnetic resonance study. J Biol Chem. 1990 Jun 15;265(17):9764-70. Pubmed
  4. Kleerekoper Q, Liu W, Choi D, Putkey JA: Identification of binding sites for bepridil and trifluoperazine on cardiac troponin C. J Biol Chem. 1998 Apr 3;273(14):8153-60. Pubmed

7. Calmodulin

Pharmacological action: unknown
Actions: binder

Calmodulin mediates the control of a large number of enzymes and other proteins by Ca(2+). Among the enzymes to be stimulated by the calmodulin-Ca(2+) complex are a number of protein kinases and phosphatases

Organism class: human
UniProt ID: P62158 Link_out
Gene: CALM1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Lamers JM, Cysouw KJ, Verdouw PD: Slow calcium channel blockers and calmodulin. Effect of felodipine, nifedipine, prenylamine and bepridil on cardiac sarcolemmal calcium pumping ATPase. Biochem Pharmacol. 1985 Nov 1;34(21):3837-43. Pubmed
  2. Lamers JM, Verdouw PD, Mas-Oliva J: The effects of felodipine and bepridil on calcium-stimulated calmodulin binding and calcium pumping ATPase of cardiac sarcolemma before and after removal of endogenous calmodulin. Mol Cell Biochem. 1987 Dec;78(2):169-76. Pubmed

8. Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B

Pharmacological action: unknown
Actions: inhibitor

Has a preference for cGMP as a substrate

Organism class: human
UniProt ID: Q01064 Link_out
Gene: PDE1B
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Lamers JM, Cysouw KJ, Verdouw PD: Slow calcium channel blockers and calmodulin. Effect of felodipine, nifedipine, prenylamine and bepridil on cardiac sarcolemmal calcium pumping ATPase. Biochem Pharmacol. 1985 Nov 1;34(21):3837-43. Pubmed

9. Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A

Pharmacological action: unknown
Actions: inhibitor

Has a higher affinity for cGMP than for cAMP

Organism class: human
UniProt ID: P54750 Link_out
Gene: PDE1A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Lamers JM, Cysouw KJ, Verdouw PD: Slow calcium channel blockers and calmodulin. Effect of felodipine, nifedipine, prenylamine and bepridil on cardiac sarcolemmal calcium pumping ATPase. Biochem Pharmacol. 1985 Nov 1;34(21):3837-43. Pubmed
Enzymes

1. Cytochrome P450 2D6

Actions: substrate

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 antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Transporters

1. Multidrug resistance protein 1

Actions: inhibitor

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Ibrahim S, Peggins J, Knapton A, Licht T, Aszalos A: Influence of antipsychotic, antiemetic, and Ca(2+) channel blocker drugs on the cellular accumulation of the anticancer drug daunorubicin: P-glycoprotein modulation. J Pharmacol Exp Ther. 2000 Dec;295(3):1276-83. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:20