title: Pyrrolo[1,2-b]pyridazines, pyrrolo[2,1-f]triazin-4(3H)-ones, and related compounds as novel corticotropin-releasing factor 1 (CRF₁) receptor antagonists.
abstract: To identify structurally novel corticotropin-releasing factor 1 (CRF(1)) receptor antagonists, a series of bicyclic core analogs pyrrolo[1,2-b]pyridazines and pyrrolo[2,1-f]triazin-4(3H)-ones, which were designed based on a monocyclic core antagonist, was synthesized and evaluated. Among the compounds tested, 2-difluoromethoxy-4-methylpyridin-5-yl analog 27 was found to show efficacy in a dose-dependent manner in an elevated plus maze test in rats. The discovery process and structure-activity relationship is presented.
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan. te.saitou@ono.co.jp
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Saito
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Obitsu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kohno
authors.forename: Isamu
authors.initials: I
authors.lastname: Sugimoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsushita
authors.forename: Taihei
authors.initials: T
authors.lastname: Nishiyama
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hirota
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takeda
authors.forename: Naoya
authors.initials: N
authors.lastname: Matsumura
authors.forename: Sonoko
authors.initials: S
authors.lastname: Ueno
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kishi
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Kagamiishi
authors.forename: Hisao
authors.initials: H
authors.lastname: Nakai
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Takaoka
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D011485:Protein Binding / Q000187:drug effects; D011724:Pyridazines / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000099052:CRF Receptor, Type 1
chemical_list: D014151:Anti-Anxiety Agents; D011724:Pyridazines; D018019:Receptors, Corticotropin-Releasing Hormone; D014227:Triazines; D000099052:CRF Receptor, Type 1