Lorcaserin

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Structural formula
Structural formula of lorcaserin
General
Non-proprietary name Lorcaserin
other names
  • APD-356
  • (1 R ) -8-Chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzazepine
  • ( R ) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -benzo [ d ] azepine ( IUPAC )
Molecular formula C 11 H 14 ClN
External identifiers / databases
CAS number
  • 616202-92-7 (Lorcaserin)
  • 846589-98-8 (Lorcaserin hydrochloride )
EC number 809-254-4
ECHA InfoCard 100.237.138
PubChem 11658860
ChemSpider 9833595
DrugBank DB04871
Wikidata Q340139
Drug information
ATC code

A08 AA11

Drug class

Appetite suppressants

properties
Molar mass
  • 195.69 g · mol -1 (lorcaserin)
  • 232.15 g mol −1 (Lorcaserin hydrochloride)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
09 - Dangerous for the environment 07 - Warning

Caution

H and P phrases H: 302-400-410
P: ?
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Lorcaserin (trade name: Belviq or Belviq XR ) is a drug from the group of serotonin agonists that was temporarily approved in the USA to suppress appetite in order to reduce weight in overweight patients.

Lorcaserin was developed by the US pharmaceutical company Arena Pharmaceuticals . The drug was approved by the US FDA in May 2012 after an initial application for approval was initially rejected in October 2010. It was marketed together with the Japanese pharmaceutical company Eisai .

In Europe, Arena withdrew the approval application for lorcaserin ( Belviq ) from the EMA ( European Medicines Agency ) at the beginning of May 2013 because the CHMP Committee of Experts had significant concerns about the approval dossier, which would certainly have led to the application being rejected. Due to cancer risks, the FDA asked Eisai in February 2020 to "voluntarily" withdraw the drug from the American market. The company responded to this request on the same day.

Clinical information

application areas

Lorcaserin is indicated as an appetite suppressant for weight loss in overweight patients. A pharmaceutical approval in Europe does not yet exist.

Side effects

The most common side effects in the Phase III clinical trials were headache , dizziness, and nausea . The frequency of characteristic side effects of other serotoninergic drugs, such as depression , anxiety disorders and thoughts of suicide , was at the placebo level . An increased risk of heart valve damage , a characteristic serious side effect of the previously used appetite suppressants fenfluramine , dexfenfluramine and aminorex , could not be observed, at least in these studies. An indication of a possibly increased cancer risk, which appeared in animal experiments in rats, initially led to the rejection of the drug approval application in the USA in 2010.

pharmacology

Pharmacodynamics

Lorcaserin is a serotonin agonist that selectively activates serotonin receptors of the 5-HT 2C type and mimics the effect of serotonin (5-HT) on this receptor. As a result, the appetite suppressing proopiomelanocortin system is activated in the hypothalamus . At the same time, the release of appetite-increasing peptides , such as neuropeptide Y and the agouti-related peptide , is inhibited. These mechanisms inhibit anabolic metabolic pathways and promote catabolic pathways. The mechanism of action is thus similar to that of other previously used appetite suppressants, such as fenfluramine. In contrast to fenfluramine, however, lorcaserin shows hardly any agonistic effects on 5-HT 2B receptors, which are associated with severe side effects such as heart valve damage and pulmonary hypertension . These results, obtained on a small scale, were confirmed in a one-year clinical study.

Pharmacokinetics

Lorcaserin is rapidly absorbed from the gastrointestinal tract into the systemic circulation. The main product of metabolism is its sulfamate , over 90% of which is excreted through the kidneys. The main metabolite is not capable of binding to 5-HT 2C receptors and does not contribute to the effect. The plasma half-life of the Lorcaserins is 10 to 11 hours.

chemistry

Stereochemistry

The benzazepine derivative lorcaserine is a chiral drug with a stereocenter. Therapeutic use is the ( R ) - enantiomer , although for the ( S 8-chloro-1-methyl-2,3,4,5-tetrahydro-1) -enantiomer of H -3-benzazepine comparable pharmacological properties were found.

synthesis

A multi-stage synthesis starting from 4-chloro-phenylethylamine is described for the production of lorcaserin . This is amidated with 2-chloropropionic acid chloride in pyridine and dichloromethane . The reaction product is converted to 8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzazepin-2-one in the presence of aluminum chloride. After reduction with the aid of borane , the racemic end product 8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H -3-benzazepine is obtained.

Analytics

The reliable qualitative and quantitative determination of Lorcaserin succeeds after appropriate sample preparation by coupling the UPLC with the mass spectrometry .

Individual evidence

  1. ↑ Template: CL Inventory / not harmonized There is not yet a harmonized classification for this substance . A labeling of No public or meaningful name is available in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on July 2, 2020, is reproduced from a self-classification by the distributor .
  2. ↑ FDA approves Belviq to treat some overweight or obese adults , FDA press release of June 27, 2012.
  3. ↑ a b Arena Pharmaceuticals press release: "FDA Issues Complete Response Letter for Lorcaserin New Drug Application" . Retrieved November 5, 2010.
  4. ↑ Questions and answers on the withdrawal of the marketing-authorization application for Belviq (PDF; 71 kB), May 31, 2013.
  5. ↑ FDA requests the withdrawal of the weight-loss drug Belviq, Belviq XR (lorcaserin) from the market , FDA Drug Safety and Availability of February 13, 2020, accessed on February 14, 2020
  6. ^ Smith SR, Weissman NJ, Anderson CM, et al. : Multicenter, placebo-controlled trial of lorcaserin for weight management . In: N. Engl. J. Med. . 363, No. 3, July 2010, pp. 245-256. doi : 10.1056 / NEJMoa0909809 . PMID 20647200 .
  7. ↑ a b c d Thomsen WJ, Grottick AJ, Menzaghi F, et al. : Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization . In: J. Pharmacol. Exp. Ther. . 325, No. 2, May 2008, pp. 577-587. doi : 10.1124 / jpet.107.133348 . PMID 18252809 .
  8. ↑ MC Fidler, M. Sanchez u. a .: A One-Year Randomized Trial of Lorcaserin for Weight Loss in Obese and Overweight Adults: The BLOSSOM Trial. In: The Journal of clinical endocrinology and metabolism . Volume 96, Number 10, October 2011, pp. 3067-3077. doi : 10.1210 / jc.2011-1256 . PMID 21795446 .
  9. ↑ a b Smith BM, Smith JM, Tsai JH, et al. : Discovery and SAR of new benzazepines as potent and selective 5-HT (2C) receptor agonists for the treatment of obesity . In: Bioorg. Med. Chem. Lett. . 15, No. 5, March 2005, pp. 1467-1470. doi : 10.1016 / j.bmcl.2004.12.080 . PMID 15713408 .
  10. ↑ Bajrai AA, Ezzeldin E, Al-Rashood KA, Raish M, Iqbal M: A Validated UPLC-MS-MS Assay for the Rapid Determination of Lorcaserin in Plasma and Brain Tissue Samples. , J Anal Toxicol. 2016 Mar; 40 (2): 133-9, PMID 26567546
  11. ↑ Hachem R, Malet-Martino M, Gilard V: First identification and quantification of lorcaserin in an herbal slimming dietary supplement. , J Pharm Biomed Anal. 2014 Sep; 98: 94-9, PMID 24905289

literature

  • Bays HE: Lorcaserin and adiposopathy: 5-HT2c agonism as a treatment for 'sick fat' and metabolic disease . In: Expert Rev Cardiovasc Ther . 7, No. 11, November 2009, pp. 1429-1445. doi : 10.1586 / erc.09.123 . PMID 19900026 .