title: Discovery of novel diarylketoxime derivatives as selective and orally active melanin-concentrating hormone 1 receptor antagonists.
abstract: Optimization of the lead 2a led to the identification of a novel diarylketoxime class of melanin-concentrating hormone 1 receptor (MCH-1R) antagonists. Our focus was directed toward improvement of hERG activity and metabolic stability. The representative derivative 4b showed potent and dose-dependent body weight reduction in diet-induced obese (DIO) C57BL/6J mice after oral administration. The synthesis and structure-activity relationships of the novel diarylketoxime MCH-1R antagonists are described.
authors.affiliation: Department of Medicinal Chemistry, Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan. takao_suzuki@merck.com
authors.forename: Takao
authors.initials: T
authors.lastname: Suzuki
authors.forename: Minoru
authors.initials: M
authors.lastname: Kameda
authors.forename: Makoto
authors.initials: M
authors.lastname: Ando
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyazoe
authors.forename: Etsuko
authors.initials: E
authors.lastname: Sekino
authors.forename: Satoru
authors.initials: S
authors.lastname: Ito
authors.forename: Kouta
authors.initials: K
authors.lastname: Masutani
authors.forename: Kaori
authors.initials: K
authors.lastname: Kamijo
authors.forename: Akihiro
authors.initials: A
authors.lastname: Takezawa
authors.forename: Minoru
authors.initials: M
authors.lastname: Moriya
authors.forename: Masahiko
authors.initials: M
authors.lastname: Ito
authors.forename: Junko
authors.initials: J
authors.lastname: Ito
authors.forename: Kazuho
authors.initials: K
authors.lastname: Nakase
authors.forename: Hiroko
authors.initials: H
authors.lastname: Matsushita
authors.forename: Akane
authors.initials: A
authors.lastname: Ishihara
authors.forename: Norihiro
authors.initials: N
authors.lastname: Takenaga
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tokita
authors.forename: Akio
authors.initials: A
authors.lastname: Kanatani
authors.forename: Nagaaki
authors.initials: N
authors.lastname: Sato
authors.forename: Takehiro
authors.initials: T
authors.lastname: Fukami
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy*; D010091:Oximes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011485:Protein Binding; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D019440:Anti-Obesity Agents; D051638:Ether-A-Go-Go Potassium Channels; C103263:MCHR1 protein, human; C491209:Mchr1 protein, mouse; D010091:Oximes; D017481:Receptors, Somatostatin