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SERTINDOLE

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.^[4]

Safety and status

USA

Abbott Labs first applied for U.S. Food and Drug Administration (FDA) approval for sertindole in 1996,^[10] but withdrew this application in 1998 following concerns over the increased risk of sudden death from QTc prolongation.^[11] In a trial of 2000 patients on taking sertindole, 27 patients died unexpectedly, including 13 sudden deaths.^[12] 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.^[13] 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.^[14] As of October 2010, the drug has not been approved by the FDA for use in the USA.^[15]

Europe

In Europe, sertindole was approved and marketed in 19 countries from 1996,^[12] but its marketing authorization was suspended by the European Medicines Agency in 1998^[16] and the drug was withdrawn from the market.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.^[17][18]

Synthesis

PAPER

I. V. Sunil Kumar¹, G. S. R. Anjaneyulu¹ and V. Hima Bindu²

¹Research and Development Centre, Aptuit Laurus Private Limited, ICICI Knowledge Park, Turkapally, Shameerpet, Hyderabad-500078, India
²Institute of Science and Technology, JNTU, Hyderabad-500072, India

Corresponding author email

Associate Editor: N. Sewald

Beilstein J. Org. Chem. 2011, 7, 29–33.

SEE AT http://beilstein-journals.org/bjoc/single/printArticle.htm?publicId=1860-5397-7-5

Sertindole is designated chemically as 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-2-imidazolidinone. Its literature synthesis (Scheme 1) [1-5] involves the copper catalyzed N-arylation of 5-chloroindole (11) with 4-fluorobromobenzene (12). The product, 5-chloro-1-(4-fluorophenyl)indole (13), on treatment with 4-piperidinone hydrochloride monohydrate (14) under acidic conditions affords 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole hydrochloride (15). Reduction of 15 in the presence of platinum oxide yields 5-chloro-1-(4-fluorophenyl)-3-(4-piperdinyl)-1H-indole (9) which on condensation with 1-(2-chloroethyl)imidazolidinone (16) in the presence of a base gives sertindole (1).

During the laboratory optimization of sertindole (1), many process related impurities were identified. The guidelines recommended by ICH state that the acceptable levels for a known and unknown compound (impurity) in the drug should be less than 0.15 and 0.10%, respectively [6]. In order to meet the stringent regulatory requirements, the impurities present in the drug substance must be identified and characterized. Literature reports [5,7-9] include impurities formed due to either over reduction (e.g., 2, 3 and 6) [5,7], incomplete reduction (e.g., 4 and 5) [5,8] or due to incomplete alkylation (e.g., 9 and 10) [5,7]. However, no synthetic details have been reported. In this context, the present study describes identification, synthesis and characterization of impurities formed during sertindole synthesis.

References

• Karamatskos, E; Lambert, M; Mulert, C; Naber, D (November 2012). “Drug safety and efficacy evaluation of sertindole for schizophrenia”. Expert Opinion on Drug Safety 11 (6): 1047–1062. doi:10.1517/14740338.2012.726984. PMID 22992213.
• “PRODUCT INFORMATION SERDOLECT® TABLETS” (PDF). TGA eBusiness Services. Lundbeck Australia Pty Ltd. 16 January 2013. Retrieved 27 October 2013.
• Juruena, MF; de Sena, EP; de Oliveira, IR (May 2011). “Sertindole in the Management of Schizophrenia” (PDF). Journal of Central Nervous System Disease 3: 75–85. doi:10.4137/JCNSD.S5729. PMC 3663609. PMID 23861640.
• Lewis, R; Bagnall, AM; Leitner, M (Jul 20, 2005). “Sertindole for schizophrenia.”. Cochrane database of systematic reviews (Online) (3): CD001715. doi:10.1002/14651858.CD001715.pub2. PMID 16034864.
• Taylor, D; Paton, C; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN 978-0-470-97948-8.
• Leucht, S; Cipriani, A; Spineli, L; Mavridis, D; Orey, D; Richter, F; Samara, M; Barbui, C; Engel, RR; Geddes, JR; Kissling, W; Stapf, MP; Lässig, B; Salanti, G; Davis, JM (September 2013). “Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis.”. Lancet 382 (9896): 951–962. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019.
• Roth, BL; Driscol, J (12 January 2011). “PDSP K_i Database”. Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 27 October 2013.
• Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman’s The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.
• http://www.trc-canada.com/detail.php?CatNum=D230095&CAS=173294-84-3&Chemical_Name=Dehydrosertindole&Mol_Formula=C24H24ClFN4O&Synonym=1-%5B2-%5B4-%5B5-Chloro-1-(4-fluorophenyl)-1H-indol-3-yl%5D-1-piperidinyl%5Dethyl%5D-1,3-dihydro-2H-Imidazol-2-one;%20Lu%2028-092
• Zeneca’s Seroquel Nears Market Approval – The Pharma Letter, 16 July 1997
• Abbott Labs Withdraws Sertindole NDA Sertindole – The Pharma Letter, 12 Jan 1998
• “WHO Pharmaceuticals Newsletter 1998, No. 03&04: Regulatory actions: Sertindole – approval application withdrawn”.
• FDA Advisory Committee provides opinion on Serdolect for the treatment of schizophrenia – Lundbeck press release, 8 Apr 2009
• Food and Drug Administration; Minutes of the Psychphamacological Drugs Advisory Committee, 7 Apr 2009
• [1]
• EU CHMP recommends lifting ban on atypical antipsychotic Serdolect (sertindole) – National electronic Library for Medicines, NHS
• COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS OPINION FOLLOWING AN ARTICLE 36 REFERRAL: SERTINDOLE – European Medicines Agency, 13 Sep 2002
• Restricted re-introduction of the atypical antipsychotic sertindole (Serdolect) – MHRA, 2002

Perregaard, J.; Arnt, J.; Boegesoe, K. P.; Hyttel, J.; Sanchez, C. (1992). “Noncataleptogenic, centrally acting dopamine D-2 and serotonin 5-HT2 antagonists within a series of 3-substituted 1-(4-fluorophenyl)-1H-indoles”. Journal of Medicinal Chemistry 35 (6): 1092. doi:10.1021/jm00084a014.

Sertindole

Systematic (IUPAC) name
1-[2-[4-[5-chloro-1-(4-fluorophenyl)-indol-3-yl]-1-piperidyl]ethyl]imidazolidin-2-one
Clinical data
AHFS/Drugs.com	International Drug Names
Pregnancy category	AU: C
Legal status	AU: Prescription Only (S4) approved for marketing in approx. 20 countries
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	75%[1]
Protein binding	99.5%[1]
Metabolism	Hepatic (mostly via CYP2D6 and CYP3A4)[2][3]
Biological half-life	3 days[2]
Excretion	Faecal (the majority), Renal (4% metabolites; 1% unchanged)[2]
Identifiers
CAS Registry Number	106516-24-9
ATC code	N05AE03
PubChem	CID: 60149
IUPHAR/BPS	98
DrugBank	DB06144
ChemSpider	54229
UNII	GVV4Z879SP
KEGG	D00561
ChEBI	CHEBI:9122
ChEMBL	CHEMBL12713
Chemical data
Formula	C24H26ClFN4O
Molecular mass	440.941

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