Melanin-concentrating hormone receptor 1 antagonists. Synthesis and structure-activity relationships of novel 3-(aminomethyl)quinolines.
It was found that 3-(aminomethyl)quinoline derivatives showed high binding affinities for melanin-concentrating hormone receptor 1 (MCHR1) with reduced affinity for serotonin receptor 2c (5-HT2c) when the dihydronaphthalene nucleus of compound 1 (human MCHR1, IC(50) = 1.9 nM; human 5-HT2c receptor, IC(50) = 0.53 nM) was replaced by other bicyclic core scaffolds. Among the synthesized compounds, 8-methylquinoline derivative 5v especially showed high binding affinity (IC(50) = 0.54 nM), potent in vitro antagonistic activity (IC(50) = 2.8 nM) for MCHR1, and negligible affinity for 5-HT2c receptor (IC(50) > 1000 nM). Oral administration of 5v significantly and dose-dependently suppressed nocturnal food intake in diet-induced obese rats and did not affect food intake in MCHR1-deficient mice. These results and rat pharmacokinetic study findings suggested that compound 5v is a highly potent, orally bioavailable, and centrally acting nonpeptide MCHR1 antagonist.
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraokahigashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. Kamata_Makoto@takeda.co.jp
Makoto
M
Kamata
Toshiro
T
Yamashita
Toshihiro
T
Imaeda
Toshio
T
Tanaka
Shinichi
S
Masada
Masahiro
M
Kamaura
Shizuo
S
Kasai
Ryoma
R
Hara
Shigekazu
S
Sasaki
Shiro
S
Takekawa
Asano
A
Asami
Tomoko
T
Kaisho
Nobuhiro
N
Suzuki
Shuntaro
S
Ashina
Hitomi
H
Ogino
Yoshihide
Y
Nakano
Yasutaka
Y
Nagisa
Koki
K
Kato
Kaneyoshi
K
Kato
Yuji
Y
Ishihara
D000284:Administration, Oral; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D004435:Eating / Q000187:drug effects; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011804:Quinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000235:genetics; D013329:Structure-Activity Relationship
C573295:4'-fluoro-N-(8-methyl-3-(1-pyrrolidinylmethyl)-7-quinolinyl)(1,1'-biphenyl)-4-carboxamide; D019440:Anti-Obesity Agents; D001549:Benzamides; C103263:MCHR1 protein, human; C491208:MCHR1 protein, rat; C491209:Mchr1 protein, mouse; D011804:Quinolines; D044405:Receptor, Serotonin, 5-HT2C; D017481:Receptors, Somatostatin