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.

Journal Article (Academic article)

A series of compounds based on 7-{[4-(2-methylphenyl)piperidin-1-yl]methyl}-6,7,8,9-tetrahydro-5 H-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.

Full Text

Duke Authors

Cited Authors

  • Yoshizumi, T; Takahashi, H; Miyazoe, H; Sugimoto, Y; Tsujita, T; Kato, T; Ito, H; Kawamoto, H; Hirayama, M; Ichikawa, D; Azuma Kanoh, T; Ozaki, S; Shibata, Y; Tani, T; Chiba, M; Ishii, Y; Okuda, S; Tadano, K; Fukuroda, T; Okamoto, O; Ohta, H

Published Date

  • July 2008

Published In

Volume / Issue

  • 51 / 13

Start / End Page

  • 4021 - 4029

International Standard Serial Number (ISSN)

  • 1520-4804

Digital Object Identifier (DOI)

  • 10.1021/jm701590h


  • English