title: Discovery of novel arylpyrazole series as potent and selective opioid receptor-like 1 (ORL1) antagonists.
abstract: 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.
authors.affiliation: Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd, Okubo-3, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Minaho
authors.initials: M
authors.lastname: Uchiyama
authors.forename: Hirokatsu
authors.initials: H
authors.lastname: Ito
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshizumi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sakoh
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Nagatomi
authors.forename: Masanori
authors.initials: M
authors.lastname: Asai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyazoe
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Tsujita
authors.forename: Mioko
authors.initials: M
authors.lastname: Hirayama
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ozaki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tani
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ishii
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ohta
authors.forename: Osamu
authors.initials: O
authors.lastname: Okamoto
mesh_terms: 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
chemical_list: 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