Referenced in: none

Automatically associated channels: Kv11.1

Title: 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.

Authors: Takashi Yoshizumi, Hirobumi Takahashi, Hiroshi Miyazoe, Yuichi Sugimoto, Tomohiro Tsujita, Tetsuya Kato, Hirokatsu Ito, Hiroshi Kawamoto, Mioko Hirayama, Daisuke Ichikawa, Tomoko Azuma-Kanoh, Satoshi Ozaki, Yoshihiro Shibata, Takeshi Tani, Masato Chiba, Yasuyuki Ishii, Shoki Okuda, Kiyoshi Tadano, Takahiro Fukuroda, Osamu Okamoto, Hisashi Ohta

Journal, date & volume: J. Med. Chem., 2008 Jul 10 , 51, 4021-9

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/18537234

Abstract
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.