Discovery of novel diarylketoxime derivatives as selective and orally active melanin-concentrating hormone 1 receptor antagonists.
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.
Suzuki
Takao
T
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
Kameda
Minoru
M
Ando
Makoto
M
Miyazoe
Hiroshi
H
Sekino
Etsuko
E
Ito
Satoru
S
Masutani
Kouta
K
Kamijo
Kaori
K
Takezawa
Akihiro
A
Moriya
Minoru
M
Ito
Masahiko
M
Ito
Junko
J
Nakase
Kazuho
K
Matsushita
Hiroko
H
Ishihara
Akane
A
Takenaga
Norihiro
N
Tokita
Shigeru
S
Kanatani
Akio
A
Sato
Nagaaki
N
Fukami
Takehiro
T
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
D019440:Anti-Obesity Agents; D051638:Ether-A-Go-Go Potassium Channels; C103263:MCHR1 protein, human; C491209:Mchr1 protein, mouse; D010091:Oximes; D017481:Receptors, Somatostatin