Discovery of novel arylpyrazole series as potent and selective opioid receptor-like 1 (ORL1) antagonists.
The synthesis and biological evaluation of new potent opioid receptor-like 1 antagonists are presented. A structure-activity relationship (SAR) study of arylpyrazole lead compound 1 obtained from library screening identified compound 31, (1S,3R)-N-{[1-(3-chloropyridin-2-yl)-5-(5-fluoro-6-methylpyridin-3-yl)-4-methyl-1H-pyrazol-3-yl]methyl}-3-fluorocyclopentanamine, which exhibits high intrinsic potency and selectivity against other opioid receptors and hERG potassium channel.
Kobayashi
Kensuke
K
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd, Okubo-3, Tsukuba, Ibaraki 300-2611, Japan.
Uchiyama
Minaho
M
Ito
Hirokatsu
H
Takahashi
Hirobumi
H
Yoshizumi
Takashi
T
Sakoh
Hiroki
H
Nagatomi
Yasushi
Y
Asai
Masanori
M
Miyazoe
Hiroshi
H
Tsujita
Tomohiro
T
Hirayama
Mioko
M
Ozaki
Satoshi
S
Tani
Takeshi
T
Ishii
Yasuyuki
Y
Ohta
Hisashi
H
Okamoto
Osamu
O
D003517:Cyclopentanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D055808:Drug Discovery; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006801:Humans; D009292:Narcotic Antagonists; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011957:Receptors, Opioid / Q000378:metabolism; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
D003517:Cyclopentanes; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C542901:N-((1-(3-chloropyridin-2-yl)-5-(5-fluoro-6-methylpyridin-3-yl)-4-methyl-1H-pyrazol-3-yl)methyl)-3-fluorocyclopentanamine; D009292:Narcotic Antagonists; D011720:Pyrazoles; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; C000722283:OPRL1 protein, human