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

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• 作者：Brian M. Smith ; Jeffrey M. Smith ; James H. Tsai ; Jeffrey A. Schultz ; Charles A. Gilson ; Scott A. Estrada ; Rita R. Chen ; Douglas M. Park ; Emily B. Prieto ; Charlemagne S. Gallardo ; Dipanjan Sengupta ; Pe
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：January 24, 2008
• 年：2008
• 卷：51
• 期：2
• 页码：305 - 313
• 全文大小：153K
• 年卷期：v.51,no.2(January 24, 2008)
• ISSN：1520-4804

文摘

The synthesis and SAR of a novel 3-benzazepine series of 5-HT_2C 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 [³H]phosphoinositol turnover: 5-HT_2C = 8.1; 5-HT_2A = 6.8; 5-HT_2B = 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 (t_1/2 = 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.