Synthesis, Structure鈥揂ctivity Relationship, and Pharmacological Studies of Novel Melanin-Concentrating Hormone Receptor 1 Antagonists 3-Aminomethylquinolines: Reducing Human Ether-a-go-go-Related Gene

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• 作者：Shizuo Kasai ; Makoto Kamata ; Shinichi Masada ; Jun Kunitomo ; Masahiro Kamaura ; Tomohiro Okawa ; Kazuaki Takami ; Hitomi Ogino ; Yoshihide Nakano ; Shuntarou Ashina ; Kaoru Watanabe ; Tomoko Kaisho ; Yumi N. Imai ; Sunghi Ryu ; Masaharu Nakayama ; Yasutaka Nagisa ; Shiro Takekawa ; Koki Kato ; Toshiki Murata ; Nobuhiro Suzuki ; Yuji Ishihara
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 10, 2012
• 年：2012
• 卷：55
• 期：9
• 页码：4336-4351
• 全文大小：567K
• 年卷期：v.55,no.9(May 10, 2012)
• ISSN：1520-4804

文摘

Recently, we discovered 3-aminomethylquinoline derivative 1, a selective, highly potent, centrally acting, and orally bioavailable human MCH receptor 1 (hMCHR1) antagonist, that inhibited food intake in F344 rats with diet-induced obesity (DIO). Subsequent investigation of 1 was discontinued because 1 showed potent hERG K⁺ channel inhibition in a patch-clamp study. To decrease hERG K⁺ channel inhibition, experiments with ligand-based drug designs based on 1 and a docking study were conducted. Replacement of the terminal p-fluorophenyl group with a cyclopropylmethoxy group, methyl group introduction on the benzylic carbon at the 3-position of the quinoline core, and employment of a [2-(acetylamino)ethyl]amino group as the amine portion eliminated hERG K⁺ channel inhibitory activity in a patch-clamp study, leading to the discovery of N-{3-[(1R)-1-{[2-(acetylamino)ethyl]amino}ethyl]-8-methylquinolin-7-yl}-4-(cyclopropylmethoxy)benzamide (R)-10h. The compound (R)-10h showed potent inhibitory activity against hMCHR1 and dose-dependently suppressed food intake in a 2-day study on DIO-F344 rats. Furthermore, practical chiral synthesis of (R)-10h was performed to determine the molecule鈥檚 absolute configuration.