Discovery of (R)-9-Ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol- 6(2H)-one, a Selective, Orally Active Agonist of the 5-HT2C Receptor

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• 作者：Dean A. Wacker ; Jeffrey G. Varnes ; Sarah E. Malmstrom ; Xueying Cao ; Chen-Pin Hung ; Thao Ung ; Ginger Wu ; Ge Zhang ; Eva Zuvich ; Michael A. Thomas ; William J. Keim ; Mary Jane Cullen ; Kenneth W. Rohrbach
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：March 22, 2007
• 年：2007
• 卷：50
• 期：6
• 页码：1365 - 1379
• 全文大小：191K
• 年卷期：v.50,no.6(March 22, 2007)
• ISSN：1520-4804

文摘

Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currentlymarketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT_2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolonecore was the identification of the appropriate substitution pattern and functional groups which led to thediscovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a5-HT_2C agonist with >300-fold functional selectivity over 5-HT_2B and >70-fold functional selectivity over5-HT_2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completelyreversed by a selective 5-HT_2C antagonist and caused a reduction in body weight gain in a 4-day rat model.