Design and synthesis of aryloxypropanolamine as β3-adrenergic receptor antagonist in cancer and lipolysis

被引：11
|
作者：
Jin, Jiyu [1 ]
Miao, Chunxiao [2 ]
Wang, Zhilong [3 ]
Zhang, Wanli [2 ]
Zhang, Xiongwen [2 ]
Xie, Xin [3 ,4 ]
Lu, Wei [1 ]
机构：
[1] East China Normal Univ, Sch Chem & Mol Engn, 3663 North Zhongshan Rd, Shanghai, Peoples R China
[2] East ChinaNormal Univ, Sch Chem & Mol Engn, Shanghai Engn Res Ctr Mol Therapeut & New Drug De, Shanghai, Peoples R China
[3] Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, CAS Key Lab Receptor Res, Shanghai, Peoples R China
[4] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
来源：
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 150卷
关键词：
beta-Adrenergic receptor; Antagonist; Cancer; Lipolysis and cachexia; MICE; METASTASIS; CACHEXIA; SWITCH;
D O I：
10.1016/j.ejmech.2018.03.032
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
beta-adrenergic receptors (beta-ARs) are broadly distributed in various tissues and regulate a panel of important physiological functions and disease states including cancer. Above all, beta(3)-adrenergic receptor (beta(3)-AR) plays a significant role in regulating lipolysis and thermogenesis in adipose tissue. In this study, we designed and synthesized a series of novel L-748,337 derivatives as selective human beta(3)-AR antagonists. Among all the tested L-748,337 analogs, compound 23d was found to display 23-fold more potent beta(3)-AR antagonist activity (EC50 = 0.5117 nM) than L-748,337 (EC50 = 11.91 nM). In vivo, compound 23d could alleviate weight loss and inhibit tumor growth in C26 tumor cachexia animal model. (C) 2018 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码：757 / 770
页数：14
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