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Identification
NameFlunarizine
Accession NumberDB04841
TypeSmall Molecule
GroupsApproved
Description

Flunarizine is a selective calcium entry blocker with calmodulin binding properties and histamine H1 blocking activity. It is effective in the prophylaxis of migraine, occlusive peripheral vascular disease, vertigo of central and peripheral origin, and as an adjuvant in the therapy of epilepsy.

Structure
Thumb
Synonyms
SynonymLanguageCode
FlunarizinaSpanishINN
FlunarizinumLatinINN
SibeliumNot AvailableNot Available
Salts
Name/CAS Structure Properties
Flunarizine dihydrochloride
Thumb
  • InChI Key: RXKMOPXNWTYEHI-RDRKJGRWSA-N
  • Monoisotopic Mass: 476.15976073
  • Average Mass: 477.417
DBSALT000382
Brand names
NameCompany
FlugeralItalfarmaco
FluxartenGlaxoSmithKline
GradientPolifarma
SibeliumJanssen
ZinasenAtralCipan
Brand mixturesNot Available
Categories
CAS number52468-60-7
WeightAverage: 404.4948
Monoisotopic: 404.206405252
Chemical FormulaC26H26F2N2
InChI KeySMANXXCATUTDDT-QPJJXVBHSA-N
InChI
InChI=1S/C26H26F2N2/c27-24-12-8-22(9-13-24)26(23-10-14-25(28)15-11-23)30-19-17-29(18-20-30)16-4-7-21-5-2-1-3-6-21/h1-15,26H,16-20H2/b7-4+
IUPAC Name
1-[bis(4-fluorophenyl)methyl]-4-[(2E)-3-phenylprop-2-en-1-yl]piperazine
SMILES
FC1=CC=C(C=C1)C(N1CCN(C\C=C\C2=CC=CC=C2)CC1)C1=CC=C(F)C=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassDiphenylmethanes
Direct parentDiphenylmethanes
Alternative parentsPhenylpropenes; Styrenes; Fluorobenzenes; Aryl Fluorides; Piperazines; Diazinanes; Tertiary Amines; Polyamines; Organofluorides
Substituentsphenylpropene; styrene; fluorobenzene; piperazine; aryl fluoride; aryl halide; 1,4-diazinane; tertiary amine; polyamine; amine; organohalogen; organonitrogen compound; organofluoride
Classification descriptionThis compound belongs to the diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
Pharmacology
IndicationUsed in the prophylaxis of migraine, occlusive peripheral vascular disease, vertigo of central and peripheral origin, and as an adjuvant in the therapy of epilepsy.
PharmacodynamicsFlunarizine is a selective calcium entry blocker with calmodulin binding properties and histamine H1 blocking activity.
Mechanism of actionFlunarizine inhibits the influx of extracellular calcium through myocardial and vascular membrane pores by physically plugging the channel. The decrease in intracellular calcium inhibits the contractile processes of smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload.
Absorption85% following oral administration.
Volume of distributionNot Available
Protein binding99% bound to plasma proteins
Metabolism

Hepatic, to two metabolites via N-dealylation and hydroxylation.

SubstrateEnzymesProduct
Flunarizine
Flunarizine metabolite M1Details
Flunarizine
Flunarizine metabolite M2Details
Flunarizine
Flunarizine metabolite M3Details
Route of eliminationNot Available
Half life18 days
ClearanceNot Available
ToxicityNot Available
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 + 0.9574
Blood Brain Barrier + 0.9789
Caco-2 permeable + 0.5893
P-glycoprotein substrate Substrate 0.7209
P-glycoprotein inhibitor I Inhibitor 0.9266
P-glycoprotein inhibitor II Non-inhibitor 0.6563
Renal organic cation transporter Inhibitor 0.7605
CYP450 2C9 substrate Non-substrate 0.8855
CYP450 2D6 substrate Substrate 0.8918
CYP450 3A4 substrate Non-substrate 0.7208
CYP450 1A2 substrate Inhibitor 0.9107
CYP450 2C9 substrate Non-inhibitor 0.9229
CYP450 2D6 substrate Inhibitor 0.9323
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate Non-inhibitor 0.9034
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.7304
Ames test Non AMES toxic 0.8902
Carcinogenicity Non-carcinogens 0.9422
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.3271 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Strong inhibitor 0.5261
hERG inhibition (predictor II) Inhibitor 0.7549
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
CapsuleOral
Prices
Unit descriptionCostUnit
Apo-Flunarizine 5 mg Capsule0.75USDcapsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point251.5Janssen, P.A.J.; U.S. Patent 3,773,939; November 20, 1973; assigned to Janssen Pharmaceutica N.V.
logP5.78BIOBYTE (1995)
Predicted Properties
PropertyValueSource
Water Solubility0.00168ALOGPS
logP5.3ALOGPS
logP6.17ChemAxon
logS-5.4ALOGPS
pKa (Strongest Basic)7.6ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area6.48 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity120.3 m3·mol-1ChemAxon
Polarizability44.2 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Matthew Peterson, Julius Remenar, Carlos Sanrame, “NOVEL FLUNARIZINE SALT FORMS AND METHODS OF MAKING AND USING THE SAME.” U.S. Patent US20080200474, issued August 21, 2008.

US20080200474
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD01303
PubChem Compound941361
PubChem Substance46507129
ChemSpider819216
BindingDB50017702
Therapeutic Targets DatabaseDAP000142
PharmGKBPA164776636
Drug Product Database846341
WikipediaFlunarizine
ATC CodesN07CA03
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
TriprolidineThe CNS depressants, Triprolidine and Flunarizine, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
Food Interactions
  • Avoid alcohol.
  • Take without regard to meals.

Targets

1. Voltage-dependent T-type calcium channel subunit alpha-1G

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent T-type calcium channel subunit alpha-1G O43497 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. Uebele VN, Nuss CE, Fox SV, Garson SL, Cristescu R, Doran SM, Kraus RL, Santarelli VP, Li Y, Barrow JC, Yang ZQ, Schlegel KA, Rittle KE, Reger TS, Bednar RA, Lemaire W, Mullen FA, Ballard JE, Tang C, Dai G, McManus OB, Koblan KS, Renger JJ: Positive allosteric interaction of structurally diverse T-type calcium channel antagonists. Cell Biochem Biophys. 2009;55(2):81-93. Epub 2009 Jul 7. Pubmed
  4. Santi CM, Cayabyab FS, Sutton KG, McRory JE, Mezeyova J, Hamming KS, Parker D, Stea A, Snutch TP: Differential inhibition of T-type calcium channels by neuroleptics. J Neurosci. 2002 Jan 15;22(2):396-403. 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. 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. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  4. Uebele VN, Nuss CE, Fox SV, Garson SL, Cristescu R, Doran SM, Kraus RL, Santarelli VP, Li Y, Barrow JC, Yang ZQ, Schlegel KA, Rittle KE, Reger TS, Bednar RA, Lemaire W, Mullen FA, Ballard JE, Tang C, Dai G, McManus OB, Koblan KS, Renger JJ: Positive allosteric interaction of structurally diverse T-type calcium channel antagonists. Cell Biochem Biophys. 2009;55(2):81-93. Epub 2009 Jul 7. Pubmed
  5. Santi CM, Cayabyab FS, Sutton KG, McRory JE, Mezeyova J, Hamming KS, Parker D, Stea A, Snutch TP: Differential inhibition of T-type calcium channels by neuroleptics. J Neurosci. 2002 Jan 15;22(2):396-403. Pubmed

3. Voltage-dependent T-type calcium channel subunit alpha-1I

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent T-type calcium channel subunit alpha-1I Q9P0X4 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. Uebele VN, Nuss CE, Fox SV, Garson SL, Cristescu R, Doran SM, Kraus RL, Santarelli VP, Li Y, Barrow JC, Yang ZQ, Schlegel KA, Rittle KE, Reger TS, Bednar RA, Lemaire W, Mullen FA, Ballard JE, Tang C, Dai G, McManus OB, Koblan KS, Renger JJ: Positive allosteric interaction of structurally diverse T-type calcium channel antagonists. Cell Biochem Biophys. 2009;55(2):81-93. Epub 2009 Jul 7. Pubmed
  4. Santi CM, Cayabyab FS, Sutton KG, McRory JE, Mezeyova J, Hamming KS, Parker D, Stea A, Snutch TP: Differential inhibition of T-type calcium channels by neuroleptics. J Neurosci. 2002 Jan 15;22(2):396-403. Pubmed

4. Histamine H1 receptor

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

Name UniProt ID Details
Histamine H1 receptor P35367 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. Taylor JE, Defeudis FV: Interactions of verapamil, D 600, flunarizine and nifedipine with cerebral histamine-receptors. Neurochem Int. 1986;9(3):379-81. Pubmed

5. Calmodulin

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Calmodulin P62158 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

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. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. 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

2. Cytochrome P450 2B6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2B6 P20813 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed

3. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. 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

4. Cytochrome P450 1A1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A1 P04798 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. 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

5. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. 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

6. Cytochrome P450 2A6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2A6 P11509 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. 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

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Drug created on September 27, 2007 07:47 / Updated on September 16, 2013 17:26