A Novel Class of Cycloalkano[b]pyridines as Potent and Orally Active Opioid Receptor-like 1 Antagonists with Minimal Binding Affinity to the hERG K+ Channel

详细信息    查看全文

• 作者：Takashi Yoshizumi ; Hirobumi Takahashi ; Hiroshi Miyazoe ; Yuichi Sugimoto ; Tomohiro Tsujita ; Tetsuya Kato ; Hirokatsu Ito ; Hiroshi Kawamoto ; Mioko Hirayama ; Daisuke Ichikawa ; Tomoko Azuma-Kanoh ; Satoshi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：July 10, 2008
• 年：2008
• 卷：51
• 期：13
• 页码：4021 - 4029
• 全文大小：222K
• 年卷期：v.51,no.13(July 10, 2008)
• ISSN：1520-4804

文摘

A series of compounds based on 7-{[4-(2-methylphenyl)piperidin-1-yl]methyl}-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-9-ol ((−)-8b), a potent and selective opioid receptor-like 1 (ORL1) antagonist, was prepared and evaluated using structure−activity relationship studies with the aim of removing its affinity to human ether-a-go-go related gene (hERG) K⁺ channel. From these studies, 10l was identified as an optimized structure with respect to ORL1 antagonist activity, and affinity to the hERG K⁺channel. Furthermore, 10l showed good in vivo antagonism with a wide therapeutic index in regards to adverse cardiovascular effects.