Optimization of benzimidazole series as opioid receptor-like 1 (ORL1) antagonists: SAR study directed toward improvement of selectivity over hERG activity.
A structure-activity relationship (SAR) study on the benzimidazole series of opioid receptor-like 1 (ORL1) antagonists related to 1 is described. Optimization of 1 by introduction of a hydrophilic substituent into the thioether part resulted in identification of potent ORL1 antagonists with high selectivity over binding affinity for hERG and other opioid receptors.
Kobayashi
Kensuke
K
Tsukuba Research Institute, Banyu Pharmaceutical Co, Ltd, Tsukuba, Ibaraki, Japan.
Kato
Tetsuya
T
Yamamoto
Izumi
I
Shimizu
Atsushi
A
Mizutani
Sayaka
S
Asai
Masanori
M
Kawamoto
Hiroshi
H
Ito
Satoru
S
Yoshizumi
Takashi
T
Hirayama
Mioko
M
Ozaki
Satoshi
S
Ohta
Hisashi
H
Okamoto
Osamu
O
D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000494:pharmacology; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D009292:Narcotic Antagonists; D011957:Receptors, Opioid / Q000378:metabolism; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
D001562:Benzimidazoles; D003510:Cyclohexanes; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor