title: Discovery of potent, selective, orally active benzoxazepine-based Orexin-2 receptor antagonists.
abstract: During our efforts to identify a series of potent, selective, orally active human Orexin-2 Receptor (OX2R) antagonists, we elucidated structure-activity relationship (SAR) on the 7-position of a benzoxazepine scaffold by utilizing Hammett σ(p) and Hansch-Fujita π value as aromatic substituent constants. The attempts led to the discovery of compound 1m, possessing good in vitro potency with over 100-fold selectivity against OX1R, good metabolic stability in human and rat liver microsome, good oral bioavailability in rats, and in vivo antagonistic activity in rats by oral administration.
authors.affiliation: Medicinal Chemistry Research Laboratories, Takeda Pharmaceutical Company, 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-1238, Japan. Fujimoto_Tatsuhiko@takeda.co.jp
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Fujimoto
authors.forename: Jun
authors.initials: J
authors.lastname: Kunitomo
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Tomata
authors.forename: Keiji
authors.initials: K
authors.lastname: Nishiyama
authors.forename: Masato
authors.initials: M
authors.lastname: Nakashima
authors.forename: Mariko
authors.initials: M
authors.lastname: Hirozane
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Yoshikubo
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hirai
authors.forename: Shogo
authors.initials: S
authors.lastname: Marui
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D064446:Orexin Receptors; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; C578626:HCRTR2 protein, human; C578627:Hcrtr1 protein, rat; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide