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Identification
NameBepridil
Accession NumberDB01244  (APRD00727)
TypeSmall Molecule
GroupsApproved, Withdrawn
Description

A long-acting, non selective, calcium channel blocker 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] It is no longer marketed in the United States, as it has been implicated in causing ventricular arrhythmias (ie. Torsade de pointes).

Structure
Thumb
Synonyms
SynonymLanguageCode
BepadinNot AvailableNot Available
BepridilNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
AngoprilNot Available
CordiumNot Available
VascorNot Available
Brand mixturesNot Available
Categories
CAS number64706-54-3
WeightAverage: 366.5396
Monoisotopic: 366.26711372
Chemical FormulaC24H34N2O
InChI KeyUIEATEWHFDRYRU-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
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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassNot Available
Direct parentBenzene and Substituted Derivatives
Alternative parentsPyrrolidines; Tertiary Amines; Polyamines; Ethers
Substituentspyrrolidine; tertiary amine; polyamine; ether; amine; organonitrogen compound
Classification descriptionThis compound belongs to the benzene and substituted derivatives. These are aromatic compounds containing at least one benzene ring.
Pharmacology
IndicationFor the treatment of hypertension, and chronic stable angina (classic effort-associated angina).
PharmacodynamicsBepridil 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 actionBepridil 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.
AbsorptionRapidly and completely absorbed after oral administration.
Volume of distributionNot Available
Protein binding99%
Metabolism

Hepatic.

Route of eliminationNot Available
Half life24-50 hours
ClearanceNot Available
ToxicityThere 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
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9859
Blood Brain Barrier + 0.9003
Caco-2 permeable + 0.5593
P-glycoprotein substrate Substrate 0.7013
P-glycoprotein inhibitor I Inhibitor 0.7951
P-glycoprotein inhibitor II Inhibitor 0.8387
Renal organic cation transporter Inhibitor 0.6774
CYP450 2C9 substrate Non-substrate 0.7898
CYP450 2D6 substrate Non-substrate 0.9117
CYP450 3A4 substrate Substrate 0.5495
CYP450 1A2 substrate Inhibitor 0.9107
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Inhibitor 0.8932
CYP450 2C19 substrate Inhibitor 0.8994
CYP450 3A4 substrate Non-inhibitor 0.8462
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.5636
Ames test Non AMES toxic 0.67
Carcinogenicity Non-carcinogens 0.8688
Biodegradation Not ready biodegradable 0.9938
Rat acute toxicity 2.4903 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Strong inhibitor 0.536
hERG inhibition (predictor II) Inhibitor 0.796
Pharmacoeconomics
Manufacturers
  • Medpointe pharmaceuticals medpointe healthcare inc
  • Johnson and johnson pharmaceutical research and development llc
PackagersNot Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral
PricesNot Available
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point128Mauvernay, R.Y., Busch, N., Moleyre, J., Monteil, A. and Simond, J.; U.S. Patent 3,962,238; June 8,1976; assigned to Centre Europeen de Recherches Mauvernay "CERM".
water solubilitySlightly solubleNot Available
logP5.2Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00655ALOGPS
logP5.33ALOGPS
logP5.49ChemAxon
logS-4.8ALOGPS
pKa (Strongest Basic)9.16ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area15.71 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity115.12 m3·mol-1ChemAxon
Polarizability43.5 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Mauvernay, R.Y., Busch, N., Moleyre, J., Monteil, A. and Simond, J.; U.S. Patent 3,962,238;
June 8,1976; assigned to Centre Europeen de Recherches Mauvernay “CERM”.

General ReferenceNot Available
External Links
ResourceLink
KEGG CompoundC06847
PubChem Compound2351
PubChem Substance46506353
ChemSpider2261
ChEBI3061
ChEMBLCHEMBL1008
Therapeutic Targets DatabaseDAP000525
PharmGKBPA164754755
IUPHAR2337
Guide to Pharmacology2337
HETBEP
RxListhttp://www.rxlist.com/cgi/generic2/bepridil.htm
Drugs.comhttp://www.drugs.com/mtm/bepridil.html
WikipediaBepridil
ATC CodesC08EA02
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
AmprenavirAmprenavir may increase the effect and toxicity of bepridil.
ArtemetherAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
AstemizoleIncreased risk of cardiotoxicity and arrhythmias
AtazanavirAtazanavir may increase the effect and toxicity of bepridil.
CisaprideIncreased risk of cardiotoxicity and arrhythmias
EtravirineBepridil (withdrawn from US. market), when used concomitantly with etravirine, may experience a decrease in serum concentration. If possible, it is recommended to monitor for decreased bepridil concentrations and therapeutic efficacy.
FosamprenavirAmprenavir increases the effect and toxicity of bepridil
GatifloxacinIncreased risk of cardiotoxicity and arrhythmias
GrepafloxacinIncreased risk of cardiotoxicity and arrhythmias
LevofloxacinIncreased risk of cardiotoxicity and arrhythmias
LumefantrineAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
MoxifloxacinIncreased risk of cardiotoxicity and arrhythmias
RitonavirRitonavir increases the effect and toxicity of bepridil
SparfloxacinIncreased risk of cardiotoxicity and arrhythmias
TelavancinAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
TerfenadineIncreased risk of cardiotoxicity and arrhythmias
TipranavirTipranavir, co-administered with Ritonavir, may increase the plasma concentration of Bepridil. Concomitant therapy is contraindicated.
Food Interactions
  • Alcohol may further decrease blood pressure and increase dizziness and drowsiness
  • Take with food to reduce nausea.

Targets

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent P/Q-type calcium channel subunit alpha-1A O00555 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent T-type calcium channel subunit alpha-1H O95180 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent calcium channel subunit alpha-2/delta-2 Q9NY47 Details

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 subunit alpha-1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Sodium/potassium-transporting ATPase subunit alpha-1 P05023 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Potassium voltage-gated channel subfamily KQT member 1 P51787 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: other

Components

Name UniProt ID Details
Troponin C, slow skeletal and cardiac muscles P63316 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: binder

Components

Name UniProt ID Details
Calmodulin P62158 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B Q01064 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A P54750 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

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
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Drug created on June 13, 2005 07:24 / Updated on March 31, 2014 15:27