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Synthesis and SAR of potent and selective tetrahydropyrazinoisoquinolinone 5-HT2C receptor agonists |
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| Authors: | Guohua Zhao 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 Jeffrey A. Robl |
| Affiliation: | Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08543-5400, USA |
| Abstract: | 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. |
| Keywords: | Tetrahydropyrazinoisoquinolinone Serotonin 5-HT2C receptor agonist Obesity 5-HT2A receptor 5-HT2B receptor Food intake reduction |
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