Discovery of novel spiro-piperidine derivatives as highly potent and selective melanin-concentrating hormone 1 receptor antagonists.
Optimization of high-throughput screening hit 1a led to the identification of a novel spiro-piperidine class of melanin-concentrating hormone 1 receptor (MCH-1R) antagonists. Compound 3c was identified as a highly potent and selective MCH-1R antagonist, which has an IC(50) value of 0.09 nM at hMCH-1R. The synthesis and structure-activity relationships of the novel spiro-piperidine MCH-1R antagonists are described.
Suzuki
Takao
T
Department of Medicinal Chemistry, Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co, Ltd, Tsukuba, Ibaraki, Japan. takao_suzuki@merck.com
Moriya
Minoru
M
Sakamoto
Toshihiro
T
Suga
Takuya
T
Kishino
Hiroyuki
H
Takahashi
Hidekazu
H
Ishikawa
Makoto
M
Nagai
Keita
K
Imai
Yumiko
Y
Sekino
Etsuko
E
Ito
Masahiko
M
Iwaasa
Hisashi
H
Ishihara
Akane
A
Tokita
Shigeru
S
Kanatani
Akio
A
Sato
Nagaaki
N
Fukami
Takehiro
T
D002460:Cell Line; D055808:Drug Discovery; D006801:Humans; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
C103263:MCHR1 protein, human; D010880:Piperidines; D017481:Receptors, Somatostatin; D013141:Spiro Compounds