Identification of 2-aminobenzimidazoles as potent melanin-concentrating hormone 1-receptor (MCH1R) antagonists.
A series of 2-aminobenzimidazole-based MCH1R antagonists was identified by core replacement of the aminoquinoline lead 1. Subsequent modification of the 2- and 5-positions led to improvement in potency and intrinsic clearance. Compound 25 exhibited good plasma and brain exposure, and attenuated MCH induced food intake at 30mg/kg PO in rats.
Moriya
Minoru
M
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd, Okubo-3, Tsukuba, Ibaraki 300-2611, Japan. minoru_moriya@merck.com
Kishino
Hiroyuki
H
Sakuraba
Shunji
S
Sakamoto
Toshihiro
T
Suga
Takuya
T
Takahashi
Hidekazu
H
Suzuki
Takao
T
Ito
Masahiko
M
Ito
Junko
J
Moriya
Ryuichi
R
Takenaga
Norihiro
N
Iwaasa
Hisashi
H
Ishihara
Akane
A
Kanatani
Akio
A
Fukami
Takehiro
T
D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D004435:Eating / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D019440:Anti-Obesity Agents; D001562:Benzimidazoles; C491208:MCHR1 protein, rat; D017481:Receptors, Somatostatin; C027391:2-aminobenzimidazole