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.
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.
Yoshizumi
Takashi
T
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd, Okubo-3, Tsukuba 300-2611, Ibaraki, Japan. takashi_yoshizumi@merck.com
Takahashi
Hirobumi
H
Miyazoe
Hiroshi
H
Sugimoto
Yuichi
Y
Tsujita
Tomohiro
T
Kato
Tetsuya
T
Ito
Hirokatsu
H
Kawamoto
Hiroshi
H
Hirayama
Mioko
M
Ichikawa
Daisuke
D
Azuma-Kanoh
Tomoko
T
Ozaki
Satoshi
S
Shibata
Yoshihiro
Y
Tani
Takeshi
T
Chiba
Masato
M
Ishii
Yasuyuki
Y
Okuda
Shoki
S
Tadano
Kiyoshi
K
Fukuroda
Takahiro
T
Okamoto
Osamu
O
Ohta
Hisashi
H
D000284:Administration, Oral; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003516:Cycloparaffins / Q000737:chemistry*; D004285:Dogs; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D009292:Narcotic Antagonists; D011485:Protein Binding; D011725:Pyridines / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry* / Q000145:classification; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
D003516:Cycloparaffins; D051638:Ether-A-Go-Go Potassium Channels; D009292:Narcotic Antagonists; D011725:Pyridines; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor