title: Novel pyrimidoazepine analogs as serotonin 5-HT(2A) and 5-HT(2C) receptor ligands for the treatment of obesity.
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-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.
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea.
authors.forename: Ha Yun
authors.initials: HY
authors.lastname: Yang
authors.forename: Jinsung
authors.initials: J
authors.lastname: Tae
authors.forename: Yong Wan
authors.initials: YW
authors.lastname: Seo
authors.forename: Yoon Jung
authors.initials: YJ
authors.lastname: Kim
authors.forename: Hye Yeon
authors.initials: HY
authors.lastname: Im
authors.forename: Gil Don
authors.initials: GD
authors.lastname: Choi
authors.forename: Heeyeong
authors.initials: H
authors.lastname: Cho
authors.forename: Woo-Kyu
authors.initials: WK
authors.lastname: Park
authors.forename: Oh Seung
authors.initials: OS
authors.lastname: Kwon
authors.forename: Yong Seo
authors.initials: YS
authors.lastname: Cho
authors.forename: Minkyung
authors.initials: M
authors.lastname: Ko
authors.forename: HyunSeo
authors.initials: H
authors.lastname: Jang
authors.forename: Jaeick
authors.initials: J
authors.lastname: Lee
authors.forename: Kihang
authors.initials: K
authors.lastname: Choi
authors.forename: Chan-Hwa
authors.initials: CH
authors.lastname: Kim
authors.forename: Jiyoun
authors.initials: J
authors.lastname: Lee
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001381:Azepines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008956:Models, Chemical; D015394:Molecular Structure; D009765:Obesity / Q000378:metabolism / Q000517:prevention & control*; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics / Q000378:metabolism*; D018490:Serotonin Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D015430:Weight Gain / Q000187:drug effects
chemical_list: C584487:2-benzyl-N-(3-chlorophenyl)-6,7,8,9-tetrahydro-5H-pyrimido(4,5-d)azepine-4-amine; D019440:Anti-Obesity Agents; D001381:Azepines; D008024:Ligands; D011743:Pyrimidines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D018490:Serotonin Agents