title: Melanin-concentrating hormone receptor 1 antagonists: synthesis, structure-activity relationship, docking studies, and biological evaluation of 2,3,4,5-tetrahydro-1H-3-benzazepine derivatives.
abstract: Melanin-concentrating hormone receptor 1 (MCHR1) antagonists have been studied as potential agents for the treatment of obesity. Initial structure-activity relationship studies of in-house hit compound 1a and subsequent optimization studies resulted in the identification of tetrahydroisoquinoline derivative 23, 1-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-[4-(4-chlorophenyl)piperidin-1-yl]butan-1-one, as a potent hMCHR1 antagonist. A homology model of hMCHR1 suggests that these compounds interact with Asn 294 and Asp 123 in the binding site of hMCHR1 to enhance binding affinity. Oral administration of compound 23 dose-dependently reduced food intake in diet-induced obesity (DIO)-F344 rats.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 26-1 Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. Kasai_Shizuo@takeda.co.jp
authors.forename: Shizuo
authors.initials: S
authors.lastname: Kasai
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kamaura
authors.forename: Makoto
authors.initials: M
authors.lastname: Kamata
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Aso
authors.forename: Hitomi
authors.initials: H
authors.lastname: Ogino
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Nakano
authors.forename: Kaoru
authors.initials: K
authors.lastname: Watanabe
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kaisho
authors.forename: Michiko
authors.initials: M
authors.lastname: Tawada
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Nagisa
authors.forename: Shiro
authors.initials: S
authors.lastname: Takekawa
authors.forename: Koki
authors.initials: K
authors.lastname: Kato
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Suzuki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishihara
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001552:Benzazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D019440:Anti-Obesity Agents; D001552:Benzazepines; D011979:Receptors, Pituitary Hormone; C092274:melanin-concentrating hormone receptor