Tricyclic dihydroquinazolinones as novel 5-HT sub(2C) selective and orally efficacious anti-obesity agents

Agonists of the 5-HT sub(2C) receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT sub(2B) receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and...

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Published in:Bioorganic & medicinal chemistry letters 2010-02, Vol.20 (3), p.1128-1133
Main Authors: Ahmad, Saleem, Ngu, Khehyong, Miller, Keith J, Wu, Ginger, Hung, Chen-Pin, Malmstrom, Sarah, Zhang, Ge, O'Tanyi, Eva, Keim, William J, Cullen, Mary Jane, Rohrbach, Kenneth W, Thomas, Michael, Ung, Thao, Qu, Qinling, Gan, Jinping, Narayanan, Rangaraj, Pelleymounter, Mary Ann, Robl, Jeffrey A
Format: Article
Language:English
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Summary:Agonists of the 5-HT sub(2C) receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT sub(2B) receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT sub(2C) agonists with no detectable agonism of the 5-HT sub(2B) receptor is described. Among these, compounds (+)- 2a and (+)- 3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing.
ISSN:0960-894X
DOI:10.1016/j.bmcl.2009.12.014