Pyrazolo[1,5-a]pyrimidines, triazolo[1,5-a]pyrimidines and their tricyclic derivatives as corticotropin-releasing factor 1 (CRF₁) receptor antagonists
2011
Saito, Tetsuji | Obitsu, Tetsuo | Minamoto, Chiaki | Sugiura, Tsuneyuki | Matsumura, Naoya | Ueno, Sonoko | Kishi, Akihiro | Katsumata, Seishi | Nakai, Hisao | Toda, Masaaki
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 (IC₅₀=4.2–418nM) and antagonist activity (EC₅₀=4.0–889nM). 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.
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