Melanin-Concentrating Hormone Receptor 1 Antagonists. Synthesis and Structure–Activity Relationships of Novel 3-(Aminomethyl)quinolines

• Published in: Journal of medicinal chemistry Vol. 55; no. 5; pp. 2353 - 2366
• Main Authors: Kamata, Makoto, Yamashita, Toshiro, Imaeda, Toshihiro, Tanaka, Toshio, Masada, Shinichi, Kamaura, Masahiro, Kasai, Shizuo, Hara, Ryoma, Sasaki, Shigekazu, Takekawa, Shiro, Asami, Asano, Kaisho, Tomoko, Suzuki, Nobuhiro, Ashina, Shuntaro, Ogino, Hitomi, Nakano, Yoshihide, Nagisa, Yasutaka, Kato, Koki, Kato, Kaneyoshi, Ishihara, Yuji
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.03.2012; Amer Chemical Soc
• Subjects: Administration, Oral; Animals; Anti-Obesity Agents - chemical synthesis; Anti-Obesity Agents - pharmacokinetics; Anti-Obesity Agents - pharmacology; Benzamides - chemical synthesis; Benzamides - pharmacokinetics; Benzamides - pharmacology; Biological Availability; Chemistry, Medicinal; Eating - drug effects; Humans; Life Sciences & Biomedicine; Mice; Mice, Knockout; Pharmacology & Pharmacy; Quinolines - chemical synthesis; Quinolines - pharmacokinetics; Quinolines - pharmacology; Rats; Receptor, Serotonin, 5-HT2C - metabolism; Receptors, Somatostatin - antagonists & inhibitors; Receptors, Somatostatin - genetics; Science & Technology; Structure-Activity Relationship; APPETITE
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm201596h

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, IC50 = 1.9 nM; human 5-HT2c receptor, IC50 = 0.53 nM) was replaced by other bicyclic core scaffolds. Among the synthesized compounds, 8-methylquinoline derivative 5v especially showed high binding affinity (IC50 = 0.54 nM), potent in vitro antagonistic activity (IC50 = 2.8 nM) for MCHR1, and negligible affinity for 5-HT2c receptor (IC50 > 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.