Synthesis and SAR of potent and selective tetrahydropyrazinoisoquinolinone 5-HT_2C receptor agonists

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• 作者：Guohua Zhao ; ^{guohua.zhao@bms.com} ; Chet Kwon ; Sharon N. Bisaha ; Philip D. Stein ; Karen A. Rossi ; Xueying Cao ; Thao Ung ; Ginger Wu ; Chen-Pin Hung ; Sarah E. Malmstrom ; Ge Zhang ; Qinling Qu ; Jinping Gan ; William J. Keim ; Mary Jane Cullen ; Kenneth W. Rohrbach ; James Devenny ; Mary Ann Pelleymounter ; Keith J. Miller ; Jeffrey A. Robl
• 关键词：Tetrahydropyrazinoisoquinolinone ; Serotonin ; 5-HT2C receptor agonist ; Obesity ; 5-HT2A receptor ; 5-HT2B receptor ; Food intake reduction
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：1 July, 2013
• 年：2013
• 卷：23
• 期：13
• 页码：3914-3919
• 全文大小：870 K

文摘

The 5-HT_2C receptor has been implicated as a critical regulator of appetite. Small molecule activation of the 5-HT_2C receptor has been shown to affect food intake and regulate body weight gain in rodent models and more recently in human clinical trials. Therefore, 5-HT_2C is a well validated target for anti-obesity therapy. The synthesis and structure-activity relationships of a series of novel tetrahydropyrazinoisoquinolinone 5-HT_2C receptor agonists are presented. Several members of this series were identified as potent 5-HT_2C receptor agonists with high functional selectivity against the 5-HT_2A and 5-HT_2B receptors and reduced food intake in an acute rat feeding model upon oral dosing.