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Identification
NamePimozide
Accession NumberDB01100  (APRD00218)
TypeSmall Molecule
GroupsApproved
Description

A diphenylbutylpiperidine that is effective as an antipsychotic agent and as an alternative to haloperidol for the suppression of vocal and motor tics in patients with Tourette syndrome. Although the precise mechanism of action is unknown, blockade of postsynaptic dopamine receptors has been postulated. (From AMA Drug Evaluations Annual, 1994, p403)

Structure
Thumb
Synonyms
SynonymLanguageCode
HalomonthNot AvailableNot Available
NeoperidoleNot AvailableNot Available
OpiranNot AvailableNot Available
OrapNot AvailableNot Available
PimozidaSpanishINN
PimozideNot AvailableNot Available
PimozidumLatinINN
SaltsNot Available
Brand names
NameCompany
NeoperidoleNot Available
OpiranNot Available
OrapNot Available
Brand mixturesNot Available
Categories
CAS number2062-78-4
WeightAverage: 461.5462
Monoisotopic: 461.227868975
Chemical FormulaC28H29F2N3O
InChI KeyYVUQSNJEYSNKRX-UHFFFAOYSA-N
InChI
InChI=1S/C28H29F2N3O/c29-22-11-7-20(8-12-22)25(21-9-13-23(30)14-10-21)4-3-17-32-18-15-24(16-19-32)33-27-6-2-1-5-26(27)31-28(33)34/h1-2,5-14,24-25H,3-4,15-19H2,(H,31,34)
IUPAC Name
1-{1-[4,4-bis(4-fluorophenyl)butyl]piperidin-4-yl}-2,3-dihydro-1H-1,3-benzodiazol-2-one
SMILES
FC1=CC=C(C=C1)C(CCCN1CCC(CC1)N1C(=O)NC2=CC=CC=C12)C1=CC=C(F)C=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassDiphenylmethanes
Direct parentDiphenylmethanes
Alternative parentsBenzimidazoles; Aminopiperidines; Fluorobenzenes; N-substituted Imidazoles; Aryl Fluorides; Tertiary Amines; Polyamines; Organofluorides
Substituentsbenzimidazole; 4-aminopiperidine; fluorobenzene; aryl fluoride; aryl halide; n-substituted imidazole; piperidine; imidazole; azole; tertiary amine; polyamine; organohalogen; amine; organofluoride; organonitrogen compound
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 for the suppression of motor and phonic tics in patients with Tourette's Disorder who have failed to respond satisfactorily to standard treatment.
PharmacodynamicsPimozide is an orally active antipsychotic drug product which shares with other antipsychotics the ability to blockade dopaminergic receptors on neurons in the central nervous system. However, receptor blockade is often accompanied by a series of secondary alterations in central dopamine metabolism and function which may contribute to both pimozide's therapeutic and untoward effects. In addition, pimozide, in common with other antipsychotic drugs, has various effects on other central nervous system receptor systems which are not fully characterized. Pimozide also has less potential for inducing sedation and hypotension as it has more specific dopamine receptor blocking activity than other neuroleptic agents (and is therefore a suitable alternative to haloperidol).
Mechanism of actionThe ability of pimozide to suppress motor and phonic tics in Tourette's Disorder is thought to be primarily a function of its dopaminergic blocking activity. Pimozide binds and inhibits the dopamine D2 receptor in the CNS.
AbsorptionGreater than 50% absorption after oral administration. Serum peak appears 6-8 hours post ingestion.
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Notable first-pass metabolism in the liver, primarily by N-dealkylation via the cytochrome P450 isoenzymes CYP3A and CYP1A2 (and possibly CYP2D6). The activity of the two major metabolites has not been determined.

Route of eliminationNot Available
Half life29 ± 10 hours (single-dose study of healthy volunteers).
ClearanceNot Available
ToxicityLD50 = 1100 mg/kg (rat, oral), 228 mg/kg (mouse, oral)
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 + 0.9974
Blood Brain Barrier + 0.9685
Caco-2 permeable - 0.8957
P-glycoprotein substrate Substrate 0.6639
P-glycoprotein inhibitor I Inhibitor 0.8842
P-glycoprotein inhibitor II Inhibitor 0.8388
Renal organic cation transporter Inhibitor 0.7255
CYP450 2C9 substrate Non-substrate 0.7829
CYP450 2D6 substrate Non-substrate 0.9112
CYP450 3A4 substrate Substrate 0.6579
CYP450 1A2 substrate Inhibitor 0.9062
CYP450 2C9 substrate Non-inhibitor 0.907
CYP450 2D6 substrate Inhibitor 0.8932
CYP450 2C19 substrate Non-inhibitor 0.9026
CYP450 3A4 substrate Inhibitor 0.686
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.9217
Ames test Non AMES toxic 0.7856
Carcinogenicity Non-carcinogens 0.9348
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.5907 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Strong inhibitor 0.6925
hERG inhibition (predictor II) Inhibitor 0.9192
Pharmacoeconomics
Manufacturers
  • Teva pharmaceuticals usa inc
Packagers
Dosage forms
FormRouteStrength
TabletOral
Prices
Unit descriptionCostUnit
Orap 1 mg tablet1.22USDtablet
Orap 2 mg tablet1.17USDtablet
Orap 4 mg Tablet0.47USDtablet
Apo-Pimozide 4 mg Tablet0.43USDtablet
Apo-Pimozide 2 mg Tablet0.24USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point214-218 °CPhysProp
water solubility10 mg/L (at 25 °C)MERCK INDEX (1996)
logP6.30HANSCH,C ET AL. (1995)
pKa8.63EL TAYAR,N ET AL. (1985)
Predicted Properties
PropertyValueSource
Water Solubility0.00173ALOGPS
logP6.36ALOGPS
logP5.83ChemAxon
logS-5.4ALOGPS
pKa (Strongest Acidic)12.9ChemAxon
pKa (Strongest Basic)8.38ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area35.58 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity132.21 m3·mol-1ChemAxon
Polarizability50.04 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
References
Synthesis ReferenceNot Available
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD00560
KEGG CompoundC07566
PubChem Compound16362
PubChem Substance46507096
ChemSpider15520
ChEBI8212
ChEMBLCHEMBL1423
Therapeutic Targets DatabaseDAP000316
PharmGKBPA450965
IUPHAR90
Guide to Pharmacology90
Drug Product Database573817
RxListhttp://www.rxlist.com/cgi/generic3/orap.htm
Drugs.comhttp://www.drugs.com/cdi/pimozide.html
WikipediaPimozide
ATC CodesN05AG02
AHFS Codes
  • 28:16.08.92
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(29 KB)
Interactions
Drug Interactions
Drug
AmprenavirAmprenavir may increase the effect and toxicity of pimozide.
AprepitantIncreased risk of cardiotoxicity and arrhythmias
ArtemetherAdditive QTc-prolongation may occur. Concomitant therapy is contraindicated.
AtazanavirThe protease inhibitor, atazanavir, may increase the effect and toxicity of pimozide.
BoceprevirBoceprevir increases levels by affecting CYP3A4 metabolism. Concomitant therapy is contraindicated.
CitalopramThe SSRI, citalopram, may increase the effect and toxicity of pimozide.
ClarithromycinIncreased risk of cardiotoxicity and arrhythmias
DonepezilPossible antagonism of action
ErythromycinIncreased risk of cardiotoxicity and arrhythmias
EscitalopramThe SSRI, escitalopram, increases the effect and toxicity of pimozide.
FluconazoleIncreased risk of cardiotoxicity and arrhythmias
FosamprenavirAmprenavir increases the effect and toxicity of pimozide
GalantaminePossible antagonism of action
ImatinibImatinib may increase the effect and toxicity of pimozide.
IndinavirThe protease inhibitor, indinavir, may increase the effect and toxicity of pimozide.
ItraconazoleIncreased risk of cardiotoxicity and arrhythmias
JosamycinIncreased risk of cardiotoxicity and arrhythmias
KetoconazoleIncreased risk of cardiotoxicity and arrhythmias
LumefantrineAdditive QTc-prolongation may occur. Concomitant therapy is contraindicated.
MesoridazineIncreased risk of cardiotoxicity and arrhythmias
NefazodoneNefazodone may increase the effect and toxicity of pimozide.
NelfinavirNelfinavir increases the effect and toxicity of pimozide
ParoxetineIncreased risk of cardiotoxicity and arrhythmias.
PosaconazoleContraindicated co-administration
RitonavirThe protease inhibitor, ritonavir, may increase the effect and toxicity of pimozide.
RivastigminePossible antagonism of action
SaquinavirThe protease inhibitor, saquinavir, may increase the effect and toxicity of pimozide.
SertralineThe SSRI, sertraline, increases the effect and toxicity of pimozide.
TacrineThe therapeutic effects of the central acetylcholinesterase inhibitor (AChEI), Tacrine, and/or the anticholinergic/antipsychotic, Pimozide, may be reduced due to antagonism. This interaction may be beneficial when the anticholinergic action is a side effect. AChEIs may also augment the central neurotoxic effect of antipsychotics. Monitor for extrapyramidal symptoms and decreased efficacy of both agents.
TacrolimusAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
TelaprevirTelaprevir increases levels by affecting CYP3A4 metabolism. Concomitant therapy is contraindicated.
TelavancinAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
TelithromycinTelithromycin may reduce clearance of Pimozide. Concomitant therapy is contraindicated.
TetrabenazineMay cause dopamine deficiency. Monitor for Tetrabenazine adverse effects.
ThioridazineIncreased risk of cardiotoxicity and arrhythmias
ThiothixeneMay cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.
TiclopidineAvoid combination with pimozide and other major CYP3A4 substrates due to the potential increase of pimozide concentration.
TipranavirTipranavir, co-administered with Ritonavir, may increase the plasma concentration of Pimozide. Concomitant therapy is contraindicated.
ToremifeneAdditive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.
TrimethobenzamideTrimethobenzamide and Pimozide, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.
TrimipramineAdditive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
TriprolidineTriprolidine and Pimozide, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Additive CNS depressant effects may also occur. Monitor for enhanced anticholinergic and CNS depressant effects.
TroleandomycinIncreased risk of cardiotoxicity and arrhythmias
TrospiumTrospium and Pimozide, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.
VoriconazoleVoriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of pimozide by decreasing its metabolism. Increased risk of QTc prolongation and development arrhythmias. Concomitant use is contraindicated.
VorinostatAdditive QTc prolongation may occur. Concomitant therapy is contraindicated.
ZileutonIncreased risk of cardiotoxicity and arrhythmias
ZiprasidoneAdditive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy should be avoided.
ZuclopenthixolAdditive QTc-prolonging effects increases risk of cardiac arrhythmias. Concomitant therapy is contraindicated.
Food Interactions
  • Grapefruit and grapefruit juice should be avoided throughout treatment. Grapefruit can increase serum levels of this product.
  • Take without regard to meals.

Targets

1. D(2) dopamine receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
D(2) dopamine receptor P14416 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Seeman P: Atypical antipsychotics: mechanism of action. Can J Psychiatry. 2002 Feb;47(1):27-38. Pubmed
  3. Silva MR, Bernardi MM, Cruz-Casallas PE, Felicio LF: Pimozide injections into the Nucleus accumbens disrupt maternal behaviour in lactating rats. Pharmacol Toxicol. 2003 Jul;93(1):42-7. Pubmed
  4. Muscat R, Sampson D, Willner P: Dopaminergic mechanism of imipramine action in an animal model of depression. Biol Psychiatry. 1990 Aug 1;28(3):223-30. Pubmed
  5. Zarrindast MR, Heidari MR: On the mechanisms by which theophylline changes core body temperature in mice. Eur J Pharmacol. 1994 May 12;257(1-2):13-20. Pubmed
  6. Freedman SB, Patel S, Marwood R, Emms F, Seabrook GR, Knowles MR, McAllister G: Expression and pharmacological characterization of the human D3 dopamine receptor. J Pharmacol Exp Ther. 1994 Jan;268(1):417-26. Pubmed
  7. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. Pubmed
  8. Murphy LL, Adrian BA, Kohli M: Inhibition of luteinizing hormone secretion by delta9-tetrahydrocannabinol in the ovariectomized rat: effect of pretreatment with neurotransmitter or neuropeptide receptor antagonists. Steroids. 1999 Sep;64(9):664-71. Pubmed

2. D(3) dopamine receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
D(3) dopamine receptor P35462 Details

References:

  1. Freedman SB, Patel S, Marwood R, Emms F, Seabrook GR, Knowles MR, McAllister G: Expression and pharmacological characterization of the human D3 dopamine receptor. J Pharmacol Exp Ther. 1994 Jan;268(1):417-26. Pubmed

3. Potassium voltage-gated channel subfamily H member 2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Potassium voltage-gated channel subfamily H member 2 Q12809 Details

References:

  1. Kang J, Wang L, Cai F, Rampe D: High affinity blockade of the HERG cardiac K(+) channel by the neuroleptic pimozide. Eur J Pharmacol. 2000 Mar 31;392(3):137-40. Pubmed
  2. Osypenko VM, Degtiar VIe, Naid’onov VG, Shuba IaM: [Blockade of HERG K+ channels expressed in Xenopus oocytes by antipsychotic agents] Fiziol Zh. 2001;47(1):17-25. Pubmed
  3. Shuba YM, Degtiar VE, Osipenko VN, Naidenov VG, Woosley RL: Testosterone-mediated modulation of HERG blockade by proarrhythmic agents. Biochem Pharmacol. 2001 Jul 1;62(1):41-9. Pubmed
  4. Kang J, Chen XL, Rampe D: The antipsychotic drugs sertindole and pimozide block erg3, a human brain K(+) channel. Biochem Biophys Res Commun. 2001 Aug 24;286(3):499-504. Pubmed

4. Calmodulin

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Calmodulin P62158 Details

References:

  1. Papadopoulos V, Brown AS, Hall PF: Calcium-calmodulin-dependent phosphorylation of cytoskeletal proteins from adrenal cells. Mol Cell Endocrinol. 1990 Dec 3;74(2):109-23. Pubmed
  2. Wang XB, Sato N, Greer MA, Greer SE, McAdams S: Role of extracellular calcium and calmodulin in prolactin secretion induced by hyposmolarity, thyrotropin-releasing hormone, and high K+ in GH4C1 cells. Acta Endocrinol (Copenh). 1990 Aug;123(2):218-24. Pubmed
  3. Strobl JS, Kirkwood KL, Lantz TK, Lewine MA, Peterson VA, Worley JF 3rd: Inhibition of human breast cancer cell proliferation in tissue culture by the neuroleptic agents pimozide and thioridazine. Cancer Res. 1990 Sep 1;50(17):5399-405. Pubmed
  4. Cimino M, Weiss B: Characteristics of the binding of phenoxybenzamine to calmodulin. Biochem Pharmacol. 1988 Jul 15;37(14):2739-45. Pubmed
  5. Mody I, Baimbridge KG, Miller JJ: Blockade of tetanic- and calcium-induced long-term potentiation in the hippocampal slice preparation by neuroleptics. Neuropharmacology. 1984 Jun;23(6):625-31. Pubmed

Enzymes

1. Cytochrome P450 3A5

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A5 P20815 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

2. Cytochrome P450 3A7

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A7 P24462 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

3. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  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 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 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

5. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 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

6. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

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

7. Cytochrome P450 2E1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2E1 P05181 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. Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J: Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery. J Med Chem. 2003 Apr 24;46(9):1716-25. Pubmed
  2. 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

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13