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

ATC Code: A08A (incomplete)
Wikipedia: Lorcaserin

On June 27^th, the FDA approved Lorcaserin hydrochloride (Tradename: Belviq^TM; 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-HT_2C 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-HT_2C receptors as compared to 5-HT_2B receptors, making it less prone to cardiovascular side-effects, associated with previous 5-HT_2C 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-HT_2C 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
MVNLRNAVHSFLVHLIGLLVWQCDISVSPVAAIVTDIFNTSDGGRFKFPDGVQNWPALSI
VIIIIMTIGGNILVIMAVSMEKKLHNATNYFLMSLAIADMLVGLLVMPLSLLAILYDYVW
PLPRYLCPVWISLDVLFSTASIMHLCAISLDRYVAIRNPIEHSRFNSRTKAIMKIAIVWA
ISIGVSVPIPVIGLRDEEKVFVNNTTCVLNDPNFVLIGSFVAFFIPLTIMVITYCLTIYV
LRRQALMLLHGHTEEPPGLSLDFLKCCKRNTAEEENSANPNQDQNARRRKKKERRPRGTM
QAINNERKASKVLGIVFFVFLIMWCPFFITNILSVLCEKSCNQKLMEKLLNVFVWIGYVC
SGINPLVYTLFNKIYRRAFSNYLRCNYKVEKKPPVRQIPRVAATALSGRELNVNIYRHTN
EPVIEKASDNEPGIEMQVENLELPVNPSSVVSERISSV

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 (t_1/2) 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 Belviq^TM is Arena Pharmaceuticals, and the full prescribing information can be found here.

Comments

Improvements in SureChEMBL's chemistry search and adoption of RDKit

Dear SureChEMBL users, If you frequently rely on our "chemistry search" feature, today brings great news! We’ve recently implemented a major update that makes your search experience faster than ever. What's New? Last week, we upgraded our structure search engine by aligning it with the core code base used in ChEMBL . This update allows SureChEMBL to leverage our FPSim2 Python package , returning results in approximately one second. The similarity search relies on 256-bit RDKit -calculated ECFP4 fingerprints, and a single instance requires approximately 1 GB of RAM to run. SureChEMBL’s FPSim2 file is not currently available for download, but we are considering generating it periodicaly and have created it once for you to try in Google Colab ! For substructure searches, we now also use an RDKit -based solution via SubstructLibrary , which returns results several times faster than our previous implementation. Additionally, structure search results are now sorted by

ChEMBL brings drug bioactivity data to the Protein Data Bank in Europe

In the quest to develop new drugs, understanding the 3D structure of molecules is crucial. Resources like the Protein Data Bank in Europe (PDBe) and the Cambridge Structural Database (CSD) provide these 3D blueprints for many biological molecules. However, researchers also need to know how these molecules interact with their biological target – their bioactivity. ChEMBL is a treasure trove of bioactivity data for countless drug-like molecules. It tells us how strongly a molecule binds to a target, how it affects a biological process, and even how it might be metabolized. But here's the catch: while ChEMBL provides extensive information on a molecule's activity and cross references to other data sources, it doesn't always tell us if a 3D structure is available for a specific drug-target complex. This can be a roadblock for researchers who need that structural information to design effective drugs. Therefore, connecting ChEMBL data with resources like PDBe and CSD is essen

Improved querying for SureChEMBL

Dear SureChEMBL users, Earlier this year we ran a survey to identify what you, the users, would like to see next in SureChEMBL. Thank you for offering your feedback! This gave us the opportunity to have some interesting discussions both internally and externally. While we can't publicly reveal precisely our plans for the coming months (everything will be delivered at the right time), we can at least say that improving the compound structure extraction quality is a priority. Unfortunately, the change won't happen overnight as reprocessing 167 millions patents takes a while. However, the good news is that the new generation of optical chemical structure recognition shows good performance, even for patent images! We hope we can share our results with you soon. So in the meantime, what are we doing? You may have noticed a few changes on the SureChEMBL main page. No more "Beta" flag since we consider the system to be stable enough (it does not mean that you will never

ChEMBL 34 is out!

We are delighted to announce the release of ChEMBL 34, which includes a full update to drug and clinical candidate drug data. This version of the database, prepared on 28/03/2024 contains: 2,431,025 compounds (of which 2,409,270 have mol files) 3,106,257 compound records (non-unique compounds) 20,772,701 activities 1,644,390 assays 15,598 targets 89,892 documents Data can be downloaded from the ChEMBL FTP site: https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_34/ Please see ChEMBL_34 release notes for full details of all changes in this release: https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_34/chembl_34_release_notes.txt New Data Sources European Medicines Agency (src_id = 66): European Medicines Agency's data correspond to EMA drugs prior to 20 January 2023 (excluding vaccines). 71 out of the 882 newly added EMA drugs are only authorised by EMA, rather than from other regulatory bodies e.g.

A python client for accessing ChEMBL web services

Motivation The CheMBL Web Services provide simple reliable programmatic access to the data stored in ChEMBL database. RESTful API approaches are quite easy to master in most languages but still require writing a few lines of code. Additionally, it can be a challenging task to write a nontrivial application using REST without any examples. These factors were the motivation for us to write a small client library for accessing web services from Python. Why Python? We choose this language because Python has become extremely popular (and still growing in use) in scientific applications; there are several Open Source chemical toolkits available in this language, and so the wealth of ChEMBL resources and functionality of those toolkits can be easily combined. Moreover, Python is a very web-friendly language and we wanted to show how easy complex resource acquisition can be expressed in Python. Reinventing the wheel? There are already some libraries providing access to ChEMBL d

The ChEMBL-og

Search This Blog