Synthesis, SAR studies, and evaluation of 1,4-benzoxazepine derivatives as selective 5-HT1A receptor agonists with neuroprotective effect: Discovery of Piclozotan.
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.
Kamei
Katsuhide
K
Daiichi Asubio Pharma Co., Ltd, 1-1-1, Wakayamadai, Mishima-gun, Osaka 618-8513, Japan. katsuhide_kamei@asubio.co.jp
Maeda
Noriko
N
Nomura
Kayoko
K
Shibata
Makoto
M
Katsuragi-Ogino
Ryoko
R
Koyama
Makoto
M
Nakajima
Mika
M
Inoue
Teruyoshi
T
Ohno
Tomochika
T
Tatsuoka
Toshio
T
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
D018696:Neuroprotective Agents; D010077:Oxazepines; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; C510463:Piclozotan