Novel pyrimidoazepine analogs as serotonin 5-HT_2A and 5-HT_2C receptor ligands for the treatment of obesity

详细信息    查看全文

• 作者：Ha Yun Yang^a ; ^b ; Jinsung Tae^b ; Yong Wan Seo^a ; Yoon Jung Kim^a ; ^c ; Hye Yeon Im^a ; ^d ; Gil Don Choi^e ; Heeyeong Cho^e ; Woo-Kyu Park^e ; Oh Seung Kwon^a ; Yong Seo Cho^a ; Minkyung Ko^a ; HyunSeo Jang^a ; Jaeick Lee^f ; Kihang Choi^c ; Chan-Hwa Kim^d ; Jiyoun Lee^g ; ^{jlee@sungshin.ac.kr} ; Ae Nim Pae^a ; ^{anpae@kist.re.kr}
• 关键词：5-HT2A antagonist ; 5-HT2C antagonist ; Obesity ; Pyrimidoazepine ; Serotonin receptor ligands
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：May, 2013
• 年：2013
• 卷：63
• 期：Complete
• 页码：558-569
• 全文大小：1213 K

文摘

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-HT_2A and 5-HT_2C 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-HT_2A and 5-HT_2C 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.