title: Identification of an orally active opioid receptor-like 1 (ORL1) receptor antagonist 4-{3-[(2R)-2,3-dihydroxypropyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-1-[(1S,3S,4R)-spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropan]-3-ylmethyl]piperidine as clinical candidate.
abstract: Our efforts to optimize prototype opioid receptor-like 1 (ORL1) antagonist 1 led to the discovery of 4-{3-[(2R)-2,3-dihydroxypropyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-1-[(1S,3S,4R)-spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropan]-3-ylmethyl]piperidine 10. 10 showed potent ORL1 antagonistic activity, excellent selectivity over other opioid receptors, and in vivo efficacy after oral dosing. Currently clinical trials of 10 are underway.
authors.affiliation: Tsukuba Research Institute, Banyu Pharmaceutical Co, Ltd, Tsukuba 300-2611, Ibaraki, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Satoh
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sagara
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sakoh
authors.forename: Masaya
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakashima
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kato
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Goto
authors.forename: Sayaka
authors.initials: S
authors.lastname: Mizutani
authors.forename: Tomoko
authors.initials: T
authors.lastname: Azuma-Kanoh
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tani
authors.forename: Shoki
authors.initials: S
authors.lastname: Okuda
authors.forename: Osamu
authors.initials: O
authors.lastname: Okamoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ozaki
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Iwasawa
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ohta
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawamoto
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D051379:Mice; D009292:Narcotic Antagonists; D010880:Piperidines / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
chemical_list: C543041:4-(3-(2,3-dihydroxypropyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-(spiro(bicyclo(2.2.1)heptane-2,1'-cyclopropan)-3-ylmethyl)piperidine; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001562:Benzimidazoles; D009292:Narcotic Antagonists; D010880:Piperidines; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor