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

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• 作者：Makoto Kamata ; Toshiro Yamashita ; Toshihiro Imaeda ; Toshio Tanaka ; Shinichi Masada ; Masahiro Kamaura ; Shizuo Kasai ; Ryoma Hara ; Shigekazu Sasaki ; Shiro Takekawa ; Asano Asami ; Tomoko Kaisho ; Nobuhiro Suzuki ; Shuntaro Ashina ; Hitomi Ogino ; Yoshihide Nakano ; Yasutaka Nagisa ; Koki Kato ; Kaneyoshi Kato ; Yuji Ishihara
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：March 8, 2012
• 年：2012
• 卷：55
• 期：5
• 页码：2353-2366
• 全文大小：530K
• 年卷期：v.55,no.5(March 8, 2012)
• ISSN：1520-4804

文摘

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.