Identification

Name
Sertindole
Accession Number
DB06144
Type
Small Molecule
Groups
Approved, Investigational, Withdrawn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 It was first marketed in 1996 in several European countries before being withdrawn two years later because of numerous cardiac adverse effects.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
  • 1-[2-[4-[5-chloro-1-(4-Fluorophenyl)-indol-3-yl]-1-piperidyl]ethyl]imidazolidin-2-one
  • SerLect
  • Sertindol
  • Sertindole
  • Sertindolum
External IDs
LU-23-174
International/Other Brands
Serdolect / Serlect
Categories
UNII
GVV4Z879SP
CAS number
106516-24-9
Weight
Average: 440.941
Monoisotopic: 440.177917386
Chemical Formula
C24H26ClFN4O
InChI Key
GZKLJWGUPQBVJQ-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

Pharmacology

Indication

Used in the treatment of schizophrenia.

Pharmacodynamics

Sertindole 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 action

Sertindole 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.

TargetActionsOrganism
AD(2) dopamine receptor
antagonist
Human
A5-hydroxytryptamine receptor 2A
antagonist
Human
A5-hydroxytryptamine receptor 2C
antagonist
Human
A5-hydroxytryptamine receptor 6
antagonist
Human
UPotassium voltage-gated channel subfamily H member 2
inhibitor
Human
UAlpha-1A adrenergic receptorNot AvailableHuman
UAlpha-1B adrenergic receptorNot AvailableHuman
UAlpha-1D adrenergic receptorNot AvailableHuman
Absorption

Orally available.

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

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

Route of elimination
Not Available
Half life

3 days

Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
2,5-Dimethoxy-4-ethylamphetamineSertindole may decrease the stimulatory activities of 2,5-Dimethoxy-4-ethylamphetamine.
2,5-Dimethoxy-4-ethylthioamphetamineSertindole may decrease the stimulatory activities of 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetamineSertindole may decrease the stimulatory activities of 3,4-Methylenedioxyamphetamine.
4-Bromo-2,5-dimethoxyamphetamineSertindole may decrease the stimulatory activities of 4-Bromo-2,5-dimethoxyamphetamine.
7-NitroindazoleThe risk or severity of adverse effects can be increased when 7-Nitroindazole is combined with Sertindole.
AbirateroneThe serum concentration of Sertindole can be increased when it is combined with Abiraterone.
AcepromazineThe risk or severity of adverse effects can be increased when Acepromazine is combined with Sertindole.
AceprometazineThe risk or severity of adverse effects can be increased when Aceprometazine is combined with Sertindole.
AcetazolamideThe risk or severity of adverse effects can be increased when Sertindole is combined with Acetazolamide.
Acetyl sulfisoxazoleThe metabolism of Sertindole can be decreased when combined with Acetyl sulfisoxazole.
Food Interactions
Not Available

References

General References
  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:15989577]
  2. Lewis R, Bagnall AM, Leitner M: Sertindole for schizophrenia. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD001715. [PubMed:16034864]
  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:16192844]
  4. Murdoch D, Keating GM: Sertindole : a review of its use in schizophrenia. CNS Drugs. 2006;20(3):233-55. [PubMed:16529528]
  5. Authors unspecified: Sertindole: new drug. Another "atypical" neuroleptic; QT prolongation. Prescrire Int. 2007 Apr;16(88):59-62. [PubMed:17458045]
  6. Lindstrom E, Levander S: Sertindole: efficacy and safety in schizophrenia. Expert Opin Pharmacother. 2006 Sep;7(13):1825-34. [PubMed:16925508]
  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:16952163]
External Links
Human Metabolome Database
HMDB0015618
KEGG Drug
D00561
KEGG Compound
C07567
PubChem Compound
60149
PubChem Substance
46504717
ChemSpider
54229
BindingDB
50001786
ChEBI
9122
ChEMBL
CHEMBL12713
Therapeutic Targets Database
DAP000832
PharmGKB
PA164784002
IUPHAR
98
Guide to Pharmacology
GtP Drug Page
Wikipedia
Sertindole
ATC Codes
N05AE03 — Sertindole

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedPreventionSchizophrenic Disorders1
3CompletedTreatmentCognition / Schizophrenic Disorders1
3CompletedTreatmentSchizophrenic Disorders3
3TerminatedTreatmentAnxiety Disorders / Dementias / Depression / Psychosomatic Disorders / Schizophrenic Disorders1
3Unknown StatusTreatmentPsychosis Nos/Other1
4Active Not RecruitingTreatmentSchizoaffective Disorders / Schizophrenia and Disorders With Psychotic Features / Schizophrenic Disorders1
4CompletedTreatmentSchizophrenic Disorders1
4TerminatedBasic ScienceSchizophrenic Disorders1
4Unknown StatusTreatmentSchizophrenic Disorders1
Not AvailableCompletedNot AvailableBipolar Disorder (BD)1
Not AvailableCompletedBasic ScienceHealthy Volunteers1
Not AvailableCompletedTreatmentSchizophrenic Disorders1
Not AvailableTerminatedBasic ScienceSchizophrenic Disorders1
Not AvailableTerminatedTreatmentSchizophrenic Disorders1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00963 mg/mLALOGPS
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 Area40.51 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity131.77 m3·mol-1ChemAxon
Polarizability47.17 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9781
Caco-2 permeable-0.7081
P-glycoprotein substrateSubstrate0.683
P-glycoprotein inhibitor IInhibitor0.903
P-glycoprotein inhibitor IIInhibitor0.7529
Renal organic cation transporterInhibitor0.6044
CYP450 2C9 substrateNon-substrate0.7898
CYP450 2D6 substrateSubstrate0.8919
CYP450 3A4 substrateSubstrate0.6803
CYP450 1A2 substrateInhibitor0.7945
CYP450 2C9 inhibitorInhibitor0.5
CYP450 2D6 inhibitorNon-inhibitor0.6155
CYP450 2C19 inhibitorInhibitor0.624
CYP450 3A4 inhibitorInhibitor0.5802
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.8995
Ames testNon AMES toxic0.6144
CarcinogenicityNon-carcinogens0.8988
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.5452 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.8038
hERG inhibition (predictor II)Inhibitor0.9186
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as phenylpyrroles. These are polycyclic aromatic compounds containing a benzene ring linked to a pyrrole ring through a CC or CN bond.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyrroles
Sub Class
Substituted pyrroles
Direct Parent
Phenylpyrroles
Alternative Parents
3-alkylindoles / Aralkylamines / Fluorobenzenes / Piperidines / Aryl chlorides / Aryl fluorides / Imidazolidinones / Heteroaromatic compounds / Ureas / Trialkylamines
show 7 more
Substituents
1-phenylpyrrole / 3-alkylindole / Indole / Indole or derivatives / Fluorobenzene / Halobenzene / Aralkylamine / Aryl chloride / Aryl fluoride / Aryl halide
show 24 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
organofluorine compound, organochlorine compound, imidazolidinone, heteroarylpiperidine, phenylindole (CHEBI:9122)

Targets

Details
1. D(2) dopamine receptor
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Potassium channel regulator activity
Specific Function
Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase.
Gene Name
DRD2
Uniprot ID
P14416
Uniprot Name
D(2) dopamine receptor
Molecular Weight
50618.91 Da
References
  1. Lindstrom E, Levander S: Sertindole: efficacy and safety in schizophrenia. Expert Opin Pharmacother. 2006 Sep;7(13):1825-34. [PubMed:16925508]
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  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. doi: 10.1007/s00213-009-1578-4. Epub 2009 Jun 9. [PubMed:19506838]
  4. Seeman P: Dopamine D2(High) receptors moderately elevated by sertindole. Synapse. 2008 May;62(5):389-93. doi: 10.1002/syn.20498. [PubMed:18293356]
  5. Cincotta SL, Rodefer JS: Emerging role of sertindole in the management of schizophrenia. Neuropsychiatr Dis Treat. 2010 Sep 7;6:429-41. [PubMed:20856607]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Virus receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5-dimethoxy-4-iodop...
Gene Name
HTR2A
Uniprot ID
P28223
Uniprot Name
5-hydroxytryptamine receptor 2A
Molecular Weight
52602.58 Da
References
  1. Lindstrom E, Levander S: Sertindole: efficacy and safety in schizophrenia. Expert Opin Pharmacother. 2006 Sep;7(13):1825-34. [PubMed:16925508]
  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:7530204]
  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:11594443]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including ergot alkaloid derivatives, 1-2,5,-dimethoxy-4-...
Gene Name
HTR2C
Uniprot ID
P28335
Uniprot Name
5-hydroxytryptamine receptor 2C
Molecular Weight
51820.705 Da
References
  1. Lindstrom E, Levander S: Sertindole: efficacy and safety in schizophrenia. Expert Opin Pharmacother. 2006 Sep;7(13):1825-34. [PubMed:16925508]
  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:11594443]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Serotonin receptor activity
Specific Function
This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor ...
Gene Name
HTR6
Uniprot ID
P50406
Uniprot Name
5-hydroxytryptamine receptor 6
Molecular Weight
46953.625 Da
References
  1. Pouzet B, Didriksen M, Arnt J: Effects of the 5-HT(6) receptor antagonist, SB-271046, in animal models for schizophrenia. Pharmacol Biochem Behav. 2002 Apr;71(4):635-43. [PubMed:11888555]
  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. doi: 10.1007/s00213-009-1578-4. Epub 2009 Jun 9. [PubMed:19506838]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function
Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the ...
Gene Name
KCNH2
Uniprot ID
Q12809
Uniprot Name
Potassium voltage-gated channel subfamily H member 2
Molecular Weight
126653.52 Da
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:9694935]
  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:11511086]
  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:11689132]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Protein heterodimerization activity
Specific Function
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) prot...
Gene Name
ADRA1A
Uniprot ID
P35348
Uniprot Name
Alpha-1A adrenergic receptor
Molecular Weight
51486.005 Da
References
  1. Lindstrom E, Levander S: Sertindole: efficacy and safety in schizophrenia. Expert Opin Pharmacother. 2006 Sep;7(13):1825-34. [PubMed:16925508]
  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:11594443]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Protein heterodimerization activity
Specific Function
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) prot...
Gene Name
ADRA1B
Uniprot ID
P35368
Uniprot Name
Alpha-1B adrenergic receptor
Molecular Weight
56835.375 Da
References
  1. Lindstrom E, Levander S: Sertindole: efficacy and safety in schizophrenia. Expert Opin Pharmacother. 2006 Sep;7(13):1825-34. [PubMed:16925508]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Alpha1-adrenergic receptor activity
Specific Function
This alpha-adrenergic receptor mediates its effect through the influx of extracellular calcium.
Gene Name
ADRA1D
Uniprot ID
P25100
Uniprot Name
Alpha-1D adrenergic receptor
Molecular Weight
60462.205 Da
References
  1. Lindstrom E, Levander S: Sertindole: efficacy and safety in schizophrenia. Expert Opin Pharmacother. 2006 Sep;7(13):1825-34. [PubMed:16925508]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
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...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Prior TI, Chue PS, Tibbo P, Baker GB: Drug metabolism and atypical antipsychotics. Eur Neuropsychopharmacol. 1999 Jun;9(4):301-9. [PubMed:10422890]
  3. Spina E, de Leon J: Metabolic drug interactions with newer antipsychotics: a comparative review. Basic Clin Pharmacol Toxicol. 2007 Jan;100(1):4-22. doi: 10.1111/j.1742-7843.2007.00017.x. [PubMed:17214606]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]

Drug created on November 19, 2007 09:49 / Updated on October 10, 2018 21:54