title: Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity.
abstract: The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [(3)H]phosphoinositol turnover: 5-HT2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.
authors: Arena Pharmaceuticals Inc., 6166 Nancy Ridge Drive, San Diego, California 92121, USA. bsmith@arenapharm.com
authors: Brian M
authors: BM
authors: Smith
authors: Jeffrey M
authors: JM
authors: Smith
authors: James H
authors: JH
authors: Tsai
authors: Jeffrey A
authors: JA
authors: Schultz
authors: Charles A
authors: CA
authors: Gilson
authors: Scott A
authors: SA
authors: Estrada
authors: Rita R
authors: RR
authors: Chen
authors: Douglas M
authors: DM
authors: Park
authors: Emily B
authors: EB
authors: Prieto
authors: Charlemagne S
authors: CS
authors: Gallardo
authors: Dipanjan
authors: D
authors: Sengupta
authors: Peter I
authors: PI
authors: Dosa
authors: Jon A
authors: JA
authors: Covel
authors: Albert
authors: A
authors: Ren
authors: Robert R
authors: RR
authors: Webb
authors: Nigel R A
authors: NR
authors: Beeley
authors: Michael
authors: M
authors: Martin
authors: Michael
authors: M
authors: Morgan
authors: Stephen
authors: S
authors: Espitia
authors: Hazel R
authors: HR
authors: Saldana
authors: Christina
authors: C
authors: Bjenning
authors: Kevin T
authors: KT
authors: Whelan
authors: Andrew J
authors: AJ
authors: Grottick
authors: Frederique
authors: F
authors: Menzaghi
authors: William J
authors: WJ
authors: Thomsen
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001552:Benzazepines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D004435:Eating / Q000187:drug effects; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008297:Male; D009765:Obesity / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058826:Serotonin 5-HT2 Receptor Agonists; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015430:Weight Gain / Q000187:drug effects
chemical_list: D019440:Anti-Obesity Agents; D001552:Benzazepines; D058826:Serotonin 5-HT2 Receptor Agonists; C506658:lorcaserin; D015544:Inositol 1,4,5-Trisphosphate