American Chemical Society
jm0612968_si_001.pdf (40.62 kB)

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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journal contribution
posted on 2007-03-22, 00:00 authored by 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, Qinling Qu, Rangaraj Narayanan, Karen Rossi, Evan Janovitz, Lois Lehman-McKeeman, Mary F. Malley, James Devenny, Mary Ann Pelleymounter, Keith J. Miller, Jeffrey A. Robl
Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a 5-HT2C agonist with >300-fold functional selectivity over 5-HT2B and >70-fold functional selectivity over 5-HT2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely reversed by a selective 5-HT2C antagonist and caused a reduction in body weight gain in a 4-day rat model.