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

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 3; pp. 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: Journal Article
• Language: English
• Published: 01.02.2010
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2009.12.014

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.