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The SARfaris: GPCR, Kinase, ADME

Friday, 29 June 2012

New Drug Approvals 2012 - Pt. XIII - Lorcaserin hydrochloride (Belviq™)

ATC Code: A08A (incomplete)
Wikipedia: Lorcaserin

On June 27th, the FDA approved Lorcaserin hydrochloride (Tradename: BelviqTM; Research Code: APD-356), a selective serotonin 2C receptor (5HT2c) agonist, for chronic weight management in adults with an initial body mass index (BMI) equal or higher than 30 kg/m2 (obese), or equal or higher than 27 kg/m2 (overweight) and with one weight-associated comorbid condition (e.g. hypertension, dyslipidemia, type 2 diabetes).

Lorcaserin is believed to decrease food consumption and promote satiety by selectively activating 5-HT2C receptors on anorexigenic pro-opiomelanocortin neurones in the hypothalamus. The exact mechanism of action is not fully established. However, at therapeutic concentrations, lorcaserin is selective for 5-HT2C receptors as compared to 5-HT2B receptors, making it less prone to cardiovascular side-effects, associated with previous 5-HT2C weight management drugs. It is the first anti-obesity drug to be approved after the withdraw of Dexfenfluramine in 1997. Given the safety issues of previous drugs, the development has focussed on safety, and with the data in hand, lorcaserin has been approved without a boxed warning.

The 5-HT2C receptor (Uniprot: P28335, ChEMBL: CHEMBL225) belongs to the G-protein coupled receptor (GPCR) type 1 family, and binds the endogenous neurotransmitter serotonin. Its activation inhibits dopamine and norepinephrine release.

>5HT2C_HUMAN 5-hydroxytryptamine receptor 2C

Lorcaserin (IUPAC: (5R)-7-chloro-5-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; Canonical smiles: C[C@H]1CNCCc2ccc(Cl)cc12; PubChem: 11658860; Chemspider: 9833595; ChEMBLID: CHEMBL360328; Standard InChI Key: XTTZERNUQAFMOF-QMMMGPOBSA-N) is a benzazepine with a single chiral center, with a molecular weight of 195.7 Da, 1 hydrogen bond acceptor, 1 hydrogen bond donor, and has an ALogP of 2.75. The compound is therefore fully rule-of-five compliant.

Lorcaserin is available as film-coated oral tablets of 10 mg, and the recommend daily dose is 20mg. The plasma half-life of lorcaserin (t1/2) is approximately 11 hr, and is moderately bound (~70%) to human plasma proteins. The absolute bioavailability of lorcaserin has not been reported.

Lorcaserin is extensively metabolised in the liver by multiple enzymatic pathways, however it inhibits CYP2D6, and therefore an increase in exposure of CYP 2D6 substrates may occur. The two major metabolites are lorcaserin sulfamate, and N-carbamoyl glucuronide lorcaserin.

As a serotonergic drug, patients should be monitored for the emergence of serotonin syndrome. For the full list of adverse reactions and drug-drug interactions please refer to the full prescribing information.

The license holder for BelviqTM is Arena Pharmaceuticals, and the full prescribing information can be found here.

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