Synthesis and SAR of potent and selective tetrahydropyrazinoisoquinolinone 5-HT2C receptor agonists

• Published in: Bioorganic & medicinal chemistry letters 2013-07, Vol.23 (13), p.3914-3919
• Main Authors: Zhao, Guohua, Kwon, Chet, Bisaha, Sharon N., Stein, Philip D., Rossi, Karen A., Cao, Xueying, Ung, Thao, Wu, Ginger, Hung, Chen-Pin, Malmstrom, Sarah E., Zhang, Ge, Qu, Qinling, Gan, Jinping, Keim, William J., Cullen, Mary Jane, Rohrbach, Kenneth W., Devenny, James, Pelleymounter, Mary Ann, Miller, Keith J., Robl, Jeffrey A.
• Format: Article
• Language: English
• Subjects: 5-HT2A receptor; 5-HT2B receptor; 5-HT2C receptor agonist; agonists; animal models; Appetite; clinical trials; food intake; Food intake reduction; humans; Obesity; rats; receptors; Serotonin; structure-activity relationships; Tetrahydropyrazinoisoquinolinone; therapeutics; weight gain
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.04.061

The 5-HT2C receptor has been implicated as a critical regulator of appetite. Small molecule activation of the 5-HT2C 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-HT2C is a well validated target for anti-obesity therapy. The synthesis and structure–activity relationships of a series of novel tetrahydropyrazinoisoquinolinone 5-HT2C receptor agonists are presented. Several members of this series were identified as potent 5-HT2C receptor agonists with high functional selectivity against the 5-HT2A and 5-HT2B receptors and reduced food intake in an acute rat feeding model upon oral dosing.