title: Synthesis, SAR studies, and evaluation of 1,4-benzoxazepine derivatives as selective 5-HT1A receptor agonists with neuroprotective effect: Discovery of Piclozotan.
abstract: A new series of 1,4-benzoxazepine derivatives was designed, synthesized, and evaluated for binding to 5-HT1A receptor and cerebral anti-ischemic effect. A lot of compounds exhibited nanomolar affinity for 5-HT1A receptor with good selectivity over both dopamine D2 and alpha1-adrenergic receptors. Among these compounds, 3-chloro-4-[4-[4-(2-pyridinyl)-1,2,3,6-tetrahydropyridin-1-yl]butyl]-1, 4-benzoxazepin-5(4H)-one (50: SUN N4057 (Piclozotan) as 2HCl salt) showed remarkable neuroprotective activity in a transient middle cerebral artery occlusion (t-MCAO) model.
authors.affiliation: Daiichi Asubio Pharma Co., Ltd, 1-1-1, Wakayamadai, Mishima-gun, Osaka 618-8513, Japan. katsuhide_kamei@asubio.co.jp
authors.forename: Katsuhide
authors.initials: K
authors.lastname: Kamei
authors.forename: Noriko
authors.initials: N
authors.lastname: Maeda
authors.forename: Kayoko
authors.initials: K
authors.lastname: Nomura
authors.forename: Makoto
authors.initials: M
authors.lastname: Shibata
authors.forename: Ryoko
authors.initials: R
authors.lastname: Katsuragi-Ogino
authors.forename: Makoto
authors.initials: M
authors.lastname: Koyama
authors.forename: Mika
authors.initials: M
authors.lastname: Nakajima
authors.forename: Teruyoshi
authors.initials: T
authors.lastname: Inoue
authors.forename: Tomochika
authors.initials: T
authors.lastname: Ohno
authors.forename: Toshio
authors.initials: T
authors.lastname: Tatsuoka
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010077:Oxazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D018696:Neuroprotective Agents; D010077:Oxazepines; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; C510463:Piclozotan