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

被引：42

作者：

Saito, Tetsuji ^{[1
]}

Obitsu, Tetsuo ^{[1
]}

Minamoto, Chiaki ^{[1
]}

Sugiura, Tsuneyuki ^{[1
]}

Matsumura, Naoya ^{[1
]}

Ueno, Sonoko ^{[1
]}

Kishi, Akihiro ^{[1
]}

Katsumata, Seishi ^{[1
]}

Nakai, Hisao ^{[1
]}

Toda, Masaaki ^{[1
]}

机构：

[1] Ono Pharmaceut Co Ltd, Minase Res Inst, Osaka 6188585, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2011年 / 19卷 / 20期

关键词：

Corticotrophin-releasing factor 1 receptor; Antagonist; MAJOR DEPRESSION; HORMONE; DMP696; PHARMACOLOGY; POTENT;

D O I：

10.1016/j.bmc.2011.08.055

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 = 4.2-418 nM) and antagonist activity (EC50 = 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. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：5955 / 5966

页数：12

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