title: Novel ORL1-selective antagonists with oral bioavailability and brain penetrability.
abstract: Following the discovery of 5-chloro-6-[piperazin-1-yl]-1H-benzimidazole as a novel pharmacophore for potent and selective ORL1 antagonist activity, optimization of this new lead by introduction of a methyl substitution on the piperazine ring resulted in a highly potent and selective, orally available, and brain penetrable ORL1 antagonist, 2-(tert-butylthio)-5-chloro-6-[(2R)-4-(2-hydroxyethyl)-2-methylpiperazin-1-yl]-1H-benzimidazole. Stereochemistry of the methyl substituent on the piperazine ring to control the functional activity of other opioid receptors is also described.
authors.affiliation: Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd, Okubo-3, Tsukuba, Ibaraki 300-2611, Japan. osamu_okamoto@merck.com
authors.forename: Osamu
authors.initials: O
authors.lastname: Okamoto
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawamoto
authors.forename: Satoru
authors.initials: S
authors.lastname: Ito
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshizumi
authors.forename: Izumi
authors.initials: I
authors.lastname: Yamamoto
authors.forename: Masaya
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shimizu
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takahashi
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ishii
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ozaki
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ohta
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D020650:Combinatorial Chemistry Techniques; D000882:Haplorhini; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009292:Narcotic Antagonists; D051381:Rats; D011957:Receptors, Opioid; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
chemical_list: C529701:2-(tert-butylthio)-5-chloro-6-((2R)-4-(2-hydroxyethyl)-2-methylpiperazin-1-yl)-1H-benzimidazole; D001562:Benzimidazoles; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor