Pyrazolo[1,5-a]pyrimidines, triazolo[1,5-a]pyrimidines and their tricyclic derivatives as corticotropin-releasing factor 1 (CRF₁) receptor antagonists

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• 作者：Tetsuji  ; Saito  ; ;   ; ^{te.saitou@ono.co.jp} ; Tetsuo  ; Obitsu ; Chiaki  ; Minamoto ; Tsuneyuki  ; Sugiura ; Naoya  ; Matsumura ; Sonoko  ; Ueno ; Akihiro  ; Kishi ; Seishi  ; Katsumata ; Hisao  ; Nakai ; Masaaki  ; Toda
• 关键词：Corticotrophin-releasing factor 1 receptor ; Antagonist
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2011
• 出版时间：15 October 2011
• 年：2011
• 卷：19
• 期：20
• 页码：5955-5966
• 全文大小：1066 K

文摘

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?b xmlns="""">27 showed binding affinity (IC₅₀ = 4.2?18 nM) and antagonist activity (EC₅₀ = 4.0?89 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¨Cactivity relationship.