Tricyclic dihydroquinazolinones as novel 5-HT2C selective and orally efficacious anti-obesity agents.

Abstract

Agonists of the 5-HT(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(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(2C) agonists with no detectable agonism of the 5-HT(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.

• Authors: Saleem Ahmad, Khehyong Ngu, Keith J Miller, Ginger Wu, Chen-pin Hung, Sarah Malmstrom, Ge Zhang, Eva O'Tanyi, William J Keim, Mary Jane Cullen, Kenneth W Rohrbach, Michael Thomas, Thao Ung, Qinling Qu, Jinping Gan, Rangaraj Narayanan, Mary Ann Pelleymounter, Jeffrey A Robl
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 20 Issue 3 Pg. 1128-33 (Feb 01 2010) ISSN: 1464-3405 [Electronic] England
• PMID: 20022752 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2009 Elsevier Ltd. All rights reserved.

Chemical References

• Anti-Obesity Agents
• Quinazolinones
• Receptor, Serotonin, 5-HT2C
• Serotonin 5-HT2 Receptor Agonists
• Serotonin Receptor Agonists

Topics

• Administration, Oral
• Animals
• Anti-Obesity Agents (administration & dosage, chemistry, metabolism)
• Eating (drug effects, physiology)
• Humans
• Male
• Obesity (drug therapy, metabolism)
• Protein Binding (physiology)
• Quinazolinones (administration & dosage, chemistry)
• Rats
• Rats, Sprague-Dawley
• Receptor, Serotonin, 5-HT2C (metabolism)
• Serotonin 5-HT2 Receptor Agonists
• Serotonin Receptor Agonists (administration & dosage, chemistry, metabolism)