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Identification
NameSertindole
Accession NumberDB06144
Typesmall molecule
Groupsapproved, withdrawn
Description

Sertindole, a neuroleptic, is one of the newer antipsychotic medications available. Serdolect is developed by the Danish pharmaceutical company H. Lundbeck. Like the other atypical antipsychotics, it has activity at dopamine and serotonin receptors in the brain. It is used in the treatment of schizophrenia. It is classified chemically as a phenylindole derivative. It was first marketed in 1996 in several European countries before being withdrawn two years later because of numerous cardiac adverse effects. It has once again been approved and should soon be available on the French and Australian market.

Structure
Thumb
Synonyms
SynonymLanguageCode
SertindolSpanishINN
SertindolumLatinINN
SaltsNot Available
Brand names
NameCompany
SerdolectNot Available
SerlectNot Available
Brand mixturesNot Available
Categories
CAS number106516-24-9
WeightAverage: 440.941
Monoisotopic: 440.177917386
Chemical FormulaC24H26ClFN4O
InChI KeyGZKLJWGUPQBVJQ-UHFFFAOYSA-N
InChI
InChI=1S/C24H26ClFN4O/c25-18-1-6-23-21(15-18)22(16-30(23)20-4-2-19(26)3-5-20)17-7-10-28(11-8-17)13-14-29-12-9-27-24(29)31/h1-6,15-17H,7-14H2,(H,27,31)
IUPAC Name
1-(2-{4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]piperidin-1-yl}ethyl)imidazolidin-2-one
SMILES
FC1=CC=C(C=C1)N1C=C(C2CCN(CCN3CCNC3=O)CC2)C2=C1C=CC(Cl)=C2
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassPyrroles
SubclassSubstituted Pyrroles
Direct parentPhenylpyrroles
Alternative parentsIndoles; Chlorobenzenes; Fluorobenzenes; Piperidines; Aryl Fluorides; Imidazolidinones; Aryl Chlorides; N-substituted Pyrroles; Tertiary Amines; Polyamines; Organofluorides; Organochlorides
Substituentsindole; indole or derivative; chlorobenzene; fluorobenzene; n-substituted pyrrole; benzene; aryl fluoride; piperidine; aryl halide; imidazolidinone; aryl chloride; imidazolidine; tertiary amine; polyamine; organochloride; organohalogen; organofluoride; amine; organonitrogen compound
Classification descriptionThis compound belongs to the phenylpyrroles. These are polycyclic aromatic compounds containing a benzene ring linked to a pyrrole ring through a CC or CN bond.
Pharmacology
IndicationUsed in the treatment of schizophrenia.
PharmacodynamicsSertindole is an atypical antipsychotic at least as effective as haloperidol and risperidone in the treatment of neuroleptic-responsive schizophrenia. Sertindole improves negative symptoms, and is also effective for the treatment of neuroleptic-resistant schizophrenia. Sertindole is generally well tolerated and is associated with a low rate of extrapyramidal symptoms (EPS).
Mechanism of actionSertindole is an antipsychotic drug with affinity for dopamine D2, serotonin 5-HT2A and 5-HT2C, and alpha1-adrenoreceptors. Preclinical studies suggest that sertindole acts preferentially on limbic and cortical dopaminergic neurons and clinical trials have confirmed that sertindole is effective at a low dopamine D2 occupancy level.
AbsorptionOrally available.
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Hepatic. Sertindole is metabolized by cytochrome P450 isoenzymes CYP 2D6 and CYP 3A4.

Route of eliminationNot Available
Half life3 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 + 1.0
Blood Brain Barrier + 0.9781
Caco-2 permeable - 0.7081
P-glycoprotein substrate Substrate 0.683
P-glycoprotein inhibitor I Inhibitor 0.903
P-glycoprotein inhibitor II Inhibitor 0.7529
Renal organic cation transporter Inhibitor 0.6044
CYP450 2C9 substrate Non-substrate 0.7898
CYP450 2D6 substrate Substrate 0.8919
CYP450 3A4 substrate Substrate 0.6803
CYP450 1A2 substrate Inhibitor 0.7945
CYP450 2C9 substrate Inhibitor 0.5
CYP450 2D6 substrate Non-inhibitor 0.6155
CYP450 2C19 substrate Inhibitor 0.624
CYP450 3A4 substrate Inhibitor 0.5802
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.8995
Ames test Non AMES toxic 0.6144
Carcinogenicity Non-carcinogens 0.8988
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.5452 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Strong inhibitor 0.8038
hERG inhibition (predictor II) Inhibitor 0.9186
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
Statesolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
water solubility9.63e-03 g/lALOGPS
logP4.29ALOGPS
logP3.77ChemAxon
logS-4.7ALOGPS
pKa (strongest acidic)14.36ChemAxon
pKa (strongest basic)8.59ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count2ChemAxon
hydrogen donor count1ChemAxon
polar surface area40.51ChemAxon
rotatable bond count5ChemAxon
refractivity131.77ChemAxon
polarizability47.17ChemAxon
number of rings5ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. Kane JM, Tamminga CA: Sertindole (Serdolect): preclinical and clinical findings of a new atypical antipsychotic. Expert Opin Investig Drugs. 1997 Nov;6(11):1729-41. Pubmed
  2. Lewis R, Bagnall AM, Leitner M: Sertindole for schizophrenia. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD001715. Pubmed
  3. Perquin LN: Treatment with the new antipsychotic sertindole for late-occurring undesirable movement effects. Int Clin Psychopharmacol. 2005 Nov;20(6):335-8. Pubmed
  4. Murdoch D, Keating GM: Sertindole : a review of its use in schizophrenia. CNS Drugs. 2006;20(3):233-55. Pubmed
  5. Sertindole: new drug. Another “atypical” neuroleptic; QT prolongation. Prescrire Int. 2007 Apr;16(88):59-62. Pubmed
  6. Lindstrom E, Levander S: Sertindole: efficacy and safety in schizophrenia. Expert Opin Pharmacother. 2006 Sep;7(13):1825-34. Pubmed
  7. Hertel P: Comparing sertindole to other new generation antipsychotics on preferential dopamine output in limbic versus striatal projection regions: mechanism of action. Synapse. 2006 Dec 1;60(7):543-52. Pubmed
External Links
ResourceLink
KEGG DrugD00561
KEGG CompoundC07567
PubChem Compound60149
PubChem Substance46504717
ChemSpider54229
ChEBI9122
ChEMBLCHEMBL12713
Therapeutic Targets DatabaseDAP000832
PharmGKBPA164784002
IUPHAR98
Guide to Pharmacology98
WikipediaSertindole
ATC CodesN05AE03
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
MesoridazineIncreased risk of cardiotoxicity and arrhythmias
ThioridazineIncreased risk of cardiotoxicity and arrhythmias
Food InteractionsNot Available

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. Lindstrom E, Levander S: Sertindole: efficacy and safety in schizophrenia. Expert Opin Pharmacother. 2006 Sep;7(13):1825-34. Pubmed
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  3. Mork A, Witten LM, Arnt J: Effect of sertindole on extracellular dopamine, acetylcholine, and glutamate in the medial prefrontal cortex of conscious rats: a comparison with risperidone and exploration of mechanisms involved. Psychopharmacology (Berl). 2009 Sep;206(1):39-49. Epub 2009 Jun 9. Pubmed
  4. Seeman P: Dopamine D2 receptors moderately elevated by sertindole. Synapse. 2008 May;62(5):389-93. Pubmed
  5. Cincotta SL, Rodefer JS: Emerging role of sertindole in the management of schizophrenia. Neuropsychiatr Dis Treat. 2010 Sep 7;6:429-41. Pubmed

2. 5-hydroxytryptamine receptor 2A

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
5-hydroxytryptamine receptor 2A P28223 Details

References:

  1. Lindstrom E, Levander S: Sertindole: efficacy and safety in schizophrenia. Expert Opin Pharmacother. 2006 Sep;7(13):1825-34. Pubmed
  2. Schreiber R, Brocco M, Millan MJ: Blockade of the discriminative stimulus effects of DOI by MDL 100,907 and the ‘atypical’ antipsychotics, clozapine and risperidone. Eur J Pharmacol. 1994 Oct 13;264(1):99-102. Pubmed
  3. Hietala J, Kuonnamaki M, Palvimaki EP, Laakso A, Majasuo H, Syvalahti E: Sertindole is a serotonin 5-HT2c inverse agonist and decreases agonist but not antagonist binding to 5-HT2c receptors after chronic treatment. Psychopharmacology (Berl). 2001 Sep;157(2):180-7. Pubmed

3. 5-hydroxytryptamine receptor 2C

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
5-hydroxytryptamine receptor 2C P28335 Details

References:

  1. Lindstrom E, Levander S: Sertindole: efficacy and safety in schizophrenia. Expert Opin Pharmacother. 2006 Sep;7(13):1825-34. Pubmed
  2. Hietala J, Kuonnamaki M, Palvimaki EP, Laakso A, Majasuo H, Syvalahti E: Sertindole is a serotonin 5-HT2c inverse agonist and decreases agonist but not antagonist binding to 5-HT2c receptors after chronic treatment. Psychopharmacology (Berl). 2001 Sep;157(2):180-7. Pubmed

4. 5-hydroxytryptamine receptor 6

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
5-hydroxytryptamine receptor 6 P50406 Details

References:

  1. Pouzet B, Didriksen M, Arnt J: Effects of the 5-HT receptor antagonist, SB-271046, in animal models for schizophrenia. Pharmacol Biochem Behav. 2002 Apr;71(4):635-43. Pubmed
  2. Mork A, Witten LM, Arnt J: Effect of sertindole on extracellular dopamine, acetylcholine, and glutamate in the medial prefrontal cortex of conscious rats: a comparison with risperidone and exploration of mechanisms involved. Psychopharmacology (Berl). 2009 Sep;206(1):39-49. Epub 2009 Jun 9. Pubmed

5. Potassium voltage-gated channel subfamily H member 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

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

References:

  1. Rampe D, Murawsky MK, Grau J, Lewis EW: The antipsychotic agent sertindole is a high affinity antagonist of the human cardiac potassium channel HERG. J Pharmacol Exp Ther. 1998 Aug;286(2):788-93. Pubmed
  2. 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
  3. Tang W, Kang J, Wu X, Rampe D, Wang L, Shen H, Li Z, Dunnington D, Garyantes T: Development and evaluation of high throughput functional assay methods for HERG potassium channel. J Biomol Screen. 2001 Oct;6(5):325-31. Pubmed

6. Alpha-1A adrenergic receptor

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Alpha-1A adrenergic receptor P35348 Details

References:

  1. Lindstrom E, Levander S: Sertindole: efficacy and safety in schizophrenia. Expert Opin Pharmacother. 2006 Sep;7(13):1825-34. Pubmed
  2. Hietala J, Kuonnamaki M, Palvimaki EP, Laakso A, Majasuo H, Syvalahti E: Sertindole is a serotonin 5-HT2c inverse agonist and decreases agonist but not antagonist binding to 5-HT2c receptors after chronic treatment. Psychopharmacology (Berl). 2001 Sep;157(2):180-7. Pubmed

7. Alpha-1B adrenergic receptor

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Alpha-1B adrenergic receptor P35368 Details

References:

  1. Lindstrom E, Levander S: Sertindole: efficacy and safety in schizophrenia. Expert Opin Pharmacother. 2006 Sep;7(13):1825-34. Pubmed

8. Alpha-1D adrenergic receptor

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Alpha-1D adrenergic receptor P25100 Details

References:

  1. Lindstrom E, Levander S: Sertindole: efficacy and safety in schizophrenia. Expert Opin Pharmacother. 2006 Sep;7(13):1825-34. 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. 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 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 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

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Drug created on November 19, 2007 09:49 / Updated on September 16, 2013 18:03