Sertindole

Sertindole

Clinical data
AHFS/Drugs.com	International Drug Names
Pregnancy category	AU: C
Routes of administration	Oral
ATC code	N05AE03 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) approved for marketing in approx 20 countries
Pharmacokinetic data
Bioavailability	75%
Protein binding	99.5%
Metabolism	Hepatic (mostly via CYP2D6 and CYP3A4)
Elimination half-life	3 days
Excretion	Faecal (the majority), Renal (4% metabolites; 1% unchanged)
Identifiers
IUPAC name 1-[2-[4-[5-chloro-1-(4-fluorophenyl)- indol-3-yl]-1-piperidyl]ethyl] imidazolidin-2-one
CAS Number	106516-24-9 Y
PubChem CID	60149
IUPHAR/BPS	98
DrugBank	DB06144 Y
ChemSpider	54229 Y
UNII	GVV4Z879SP
KEGG	D00561 Y
ChEBI	CHEBI:9122 Y
ChEMBL	ChEMBL12713 Y
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C24H26ClFN4O
Molar mass	440.941
3D model (JSmol)	Interactive image
SMILES Fc1ccc(cc1)n3c2ccc(Cl)cc2c(c3)C5CCN(CCN4C(=O)NCC4)CC5
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) Y Key:GZKLJWGUPQBVJQ-UHFFFAOYSA-N Y
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]

Overview

Sertindole (brand names: Serdolect, and Serlect) is an antipsychotic medication. Sertindole was developed by the Danish pharmaceutical company H. Lundbeck and marketed under license by Abbott Labs. Like 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.

Sertindole is not approved for use in the United States.

Medical Uses

Sertindole appears effective as an antipsychotic in schizophrenia.

Adverse Effects

Very common (>10% incidence) adverse effects include:

• Headache
• Ejaculation failure
• Insomnia
• Dizziness

Common (1-10% incidence) adverse effects include:

• Urine that tests positive for red and/or white blood cells
• Sedation (causes less sedation than most antipsychotic drugs according to a recent meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs. Causes only slightly [and non-significantly] more sedation than amisulpride and paliperidone)
• Ejaculation disorder
• Erectile dysfunction
• Orthostatic hypotension
• Weight gain (which it seems to possess a similar propensity for causing as quetiapine)

Uncommon (0.1-1% incidence) adverse effects include:

• Substernal chest pain
• Face oedema
• Flu syndrome
• Neck rigidity
• Pallor
• Peripheral vascular disorder
• Syncope
• Torsades de Pointes
• Vasodilation
• Suicide attempt
• Amnesia
• Anxiety
• Ataxia
• Confusion
• Incoordination
• Libido decreased
• Libido increased
• Miosis
• Nystagmus
• Personality disorder
• Psychosis
• Reflexes decreased
• Reflexes increased
• Stupor
• Suicidal tendency
• Urinary retention
• Vertigo
• Diabetes mellitus
• Abnormal stools
• Gastritis
• Gingivitis
• Glossitis
• Increased appetite
• Mouth ulceration
• Rectal disorder
• Rectal haemorrhage
• Stomatitis
• Tongue disorder
• Ulcerative stomatitis
• Anaemia
• Ecchymosis
• Hypochromic anaemia
• Leukopenia
• Hyperglycaemia
• Hyperlipemia
• Oedema
• Bone pain
• Myasthenia
• Twitching
• Bronchitis
• Hyperventilation
• Pneumonia
• Sinusitis
• Furunculosis
• Herpes simplex
• Nail disorder
• Psoriasis
• Pustular Rash
• Skin discolouration
• Skin hypertrophy
• Skin ulcer
• Abnormal vision
• Keratoconjunctivitis
• Lacrimation disorder
• Otitis externa
• Pupillary disorder
• Taste perversion
• Anorgasmia
• Penis disorder (gs)
• Urinary urgency
• Hyperprolactinaemia (which it seems to cause with a higher propensity than most other atypical antipsychotics do)
• Seizures
• Galactorrhoea

Rare (<0.1% incidence) adverse effects include:

• Neuroleptic malignant syndrome
• Tardive dyskinesia

Unknown frequency adverse events include:

• Extrapyramidal side effects (EPSE; e.g. dystonia, akathisia, muscle rigidity, parkinsonism, etc. These adverse effects are probably uncommon/rare according to a recent meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs which found it had the 2nd lowest effect size for causing EPSE)
• Venous thromboembolism
• QT interval prolongation (probably common; in a recent meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs it was found to be the most prone to causing QT interval prolongation)

Pharmacology

Biologic protein	Binding affinity (Ki[nM])	Notes
5-HT1A	280
5-HT1B	60
5-HT1D	96
5-HT1E	430
5-HT1F	360
5-HT2A	0.39	The receptor believed to mediate the atypicality of atypical antipsychotics.
5-HT2C	0.9	Likely responsible for its propensity for causing weight gain.
5-HT6	5.4
5-HT7	28
α1A	1.8	Likely responsible for the orthostatic hypotension seen in patients on sertindole.
α2A	640
α2B	450
α2C	450
β1	5000
β2	5000
M1	>10000
M3	2692
D2	2.35	Believed to be responsible for the drug's efficacy against positive symptoms.
D3	2.30
D4	4.92
HERG	3
H1	130
NK1	1000

Safety and status

USA

Abbott Labs first applied for U.S. Food and Drug Administration (FDA) approval for sertindole in 1996, but withdrew this application in 1998 following concerns over the increased risk of sudden death from QTc prolongation. In a trial of 2000 patients on taking sertindole, 27 patients died unexpectedly, including 13 sudden deaths. Lundbeck cites the results of the Sertindole Cohort Prospective (SCoP) study of 10,000 patients to support its claim that although sertindole does increase the QTc interval, this is not associated with increased rates of cardiac arrhythmias, and that patients on sertindole had the same overall mortality rate as those on risperidone. Nevertheless in April 2009 an FDA advisory panel voted 13-0 that sertindole was effective in the treatment of schizophrenia but 12-1 that it had not been shown to be acceptably safe. As of October 2010, the drug has not been approved by the FDA for use in the USA.

Europe

In Europe, sertindole was approved and marketed in 19 countries from 1996, but its marketing authorization was suspended by the European Medicines Agency in 1998 and the drug was withdrawn from the market. In 2002, based on new data, the EMA's CHMP suggested that Sertindole could be reintroduced for restricted use in clinical trials, with strong safeguards including extensive contraindications and warnings for patients at risk of cardiac dysrhythmias, a recommended reduction in maximum dose from 24 mg to 20 mg in all but exceptional cases, and extensive ECG monitoring requirement before and during treatment.

Synthesis

Sertindole synthesis: