Synthesis and SAR of potent and selective tetrahydropyrazinoisoquinolinone 5-HT(2C) 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: Animals; Crystallography, X-Ray; Dose-Response Relationship, Drug; Eating - drug effects; Humans; Isoquinolines - chemical synthesis; Isoquinolines - chemistry; Isoquinolines - pharmacology; Models, Molecular; Molecular Structure; Pyrazines - chemical synthesis; Pyrazines - chemistry; Pyrazines - pharmacology; Rats; Receptor, Serotonin, 5-HT2C - metabolism; Structure-Activity Relationship
• ISSN: 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.