title: Pyrazolo[1,5-a]pyrimidines, triazolo[1,5-a]pyrimidines and their tricyclic derivatives as corticotropin-releasing factor 1 (CRF₁) receptor antagonists.
abstract: To identify structurally novel CRF1 receptor antagonists, a series of bicyclic core antagonists, pyrazolo[1,5-a]pyrimidines, triazolo[1,5-a]pyrimidines, imidazo[1,2-a]pyrimidines and pyrazolo[1,5-a][1,3,5]triazines were designed, synthesized and evaluated as CRF1 receptor antagonists. Compounds 2-27 showed binding affinity (IC(50)=4.2-418 nM) and antagonist activity (EC(50)=4.0-889 nM). Compound 5 was found to show oral efficacy in an Elevated Plus Maze test in rats. Further chemical modification of them led us to discovery of the tricyclic core antagonists pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidines. The discovery process of these compounds is presented, as is the study of the structure-activity relationship.
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd, 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: Chiaki
authors.initials: C
authors.lastname: Minamoto
authors.forename: Tsuneyuki
authors.initials: T
authors.lastname: Sugiura
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: Seishi
authors.initials: S
authors.lastname: Katsumata
authors.forename: Hisao
authors.initials: H
authors.lastname: Nakai
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toda
mesh_terms: D000818:Animals; D006801:Humans; D007700:Kinetics; D008297:Male; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013329:Structure-Activity Relationship; D000099052:CRF Receptor, Type 1
chemical_list: D011743:Pyrimidines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1