Novel pyrimidoazepine analogs as serotonin 5-HT2A and 5-HT 2C receptor ligands for the treatment of obesity

Ha Yun Yang, Jinsung Tae, Yong Wan Seo, Yoon Jung Kim, Hye Yeon Im, Gil Don Choi, Heeyeong Cho, Woo Kyu Park, Oh Seung Kwon, Yong Seo Cho, Minkyung Ko, Hyunseo Jang, Jaeick Lee, Kihang Choi, Chan Hwa Kim, Jiyoun Lee, Ae Nim Pae

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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-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-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.

Original languageEnglish
Pages (from-to)558-569
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume63
DOIs
Publication statusPublished - 2013 Mar 28

Fingerprint

Anti-Obesity Agents
Receptor, Serotonin, 5-HT2C
Serotonin
Obesity
Ligands
Public health
Medical problems
Bioactivity
Weight Gain
Eating
Body Weight
Inhibitory Concentration 50
Weight Loss
Public Health
Exercise
Control Groups
Therapeutics
serotonin 5 receptor

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

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. / Novel pyrimidoazepine analogs as serotonin 5-HT2A and 5-HT 2C receptor ligands for the treatment of obesity. In: European Journal of Medicinal Chemistry. 2013 ; Vol. 63. pp. 558-569.
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abstract = "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-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-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.",
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Yang, HY, Tae, J, Seo, YW, Kim, YJ, Im, HY, Choi, GD, Cho, H, Park, WK, Kwon, OS, Cho, YS, Ko, M, Jang, H, Lee, J, Choi, K, Kim, CH, Lee, J & Pae, AN 2013, 'Novel pyrimidoazepine analogs as serotonin 5-HT2A and 5-HT 2C receptor ligands for the treatment of obesity', European Journal of Medicinal Chemistry, vol. 63, pp. 558-569. https://doi.org/10.1016/j.ejmech.2013.02.020

Novel pyrimidoazepine analogs as serotonin 5-HT2A and 5-HT 2C receptor ligands for the treatment of obesity. / 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.

In: European Journal of Medicinal Chemistry, Vol. 63, 28.03.2013, p. 558-569.

Research output: Contribution to journalArticle

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T1 - Novel pyrimidoazepine analogs as serotonin 5-HT2A and 5-HT 2C receptor ligands for the treatment of obesity

AU - Yang, Ha Yun

AU - Tae, Jinsung

AU - Seo, Yong Wan

AU - Kim, Yoon Jung

AU - Im, Hye Yeon

AU - Choi, Gil Don

AU - Cho, Heeyeong

AU - Park, Woo Kyu

AU - Kwon, Oh Seung

AU - Cho, Yong Seo

AU - Ko, Minkyung

AU - Jang, Hyunseo

AU - Lee, Jaeick

AU - Choi, Kihang

AU - Kim, Chan Hwa

AU - Lee, Jiyoun

AU - Pae, Ae Nim

PY - 2013/3/28

Y1 - 2013/3/28

N2 - 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-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-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.

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