Novel pyrimidoazepine analogs as serotonin 5-HT2A and 5-HT2C receptor ligands for the treatment of obesity

Obesity is one of the most serious public health problems worldwide in the 21st century. Current therapeutic treatment for obesity is mostly focused on preventive measures involving dietary control and physical exercises in combination with anti-obesity medications. However, most of these anti-obesi...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2013-05, Vol.63, p.558-569
Main Authors: Yang, Ha Yun, Tae, Jinsung, Seo, Yong Wan, Kim, Yoon Jung, Im, Hye Yeon, Choi, Gil Don, Cho, Heeyeong, Park, Woo-Kyu, Kwon, Oh Seung, Cho, Yong Seo, Ko, Minkyung, Jang, HyunSeo, Lee, Jaeick, Choi, Kihang, Kim, Chan-Hwa, Lee, Jiyoun, Pae, Ae Nim
Format: Article
Language:English
Subjects:
5-HT2A antagonist
5-HT2C antagonist
Obesity
Pyrimidoazepine
Serotonin receptor ligands
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Summary:Obesity is one of the most serious public health problems worldwide in the 21st century. Current therapeutic treatment for obesity is mostly focused on preventive measures involving dietary control and physical exercises in combination with anti-obesity medications. However, most of these anti-obesity medications have little or no effect on weight loss, and some cases have demonstrated fatal side effects. Due to the urgent need for highly potent and selective anti-obesity agents, the serotonin receptors (5-HTR) have been the focus of much interest as a novel therapeutic target. In this report, we have developed pyrimidoazepine analogs targeting the 5-HT2A and 5-HT2C receptors and evaluated their biological activity in vitro and in vivo as novel anti-obesity agents. We were able to identify 6p as the most potent 5-HT2A and 5-HT2C ligand in vitro (IC50 = 3 nM and 2.3 nM, respectively), and this compound also demonstrated the greatest potency in vivo. In an acute obesity model, mice treated with 6p showed significant decrease in body weight gain and food intake over approximately 77–94% compared to a control group. In a chronic obesity model, mice treated with 6p also showed a marked decrease in food intake and body weight gain. [Display omitted] ► Novel 5-HT receptor ligands were developed for anti-obesity medication. ► In vitro biological activity against 5-HT2A and 5-HT2C receptors were evaluated. ► Significant in vivo effect in acute and chronic obesity model of mice was observed.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2013.02.020