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Eur J Med Chem. 2018 Apr 25;150:757-770. doi: 10.1016/j.ejmech.2018.03.032. Epub 2018 Mar 17.

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

Author information

1
School of Chemistry and Molecular Engineering, East China Normal University, 3663, North Zhongshan Road, Shanghai, China.
2
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East ChinaNormal University, Shanghai, China.
3
CAS Key Laboratory of Receptor Research, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
4
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East ChinaNormal University, Shanghai, China. Electronic address: xwzhang@sat.ecnu.edu.cn.
5
CAS Key Laboratory of Receptor Research, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. Electronic address: xxie@simm.ac.cn.
6
School of Chemistry and Molecular Engineering, East China Normal University, 3663, North Zhongshan Road, Shanghai, China. Electronic address: wlu@chem.ecnu.edu.cn.

Abstract

β-adrenergic receptors (β-ARs) are broadly distributed in various tissues and regulate a panel of important physiological functions and disease states including cancer. Above all, β3-adrenergic receptor (β3-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 β3-AR antagonists. Among all the tested L-748,337 analogs, compound 23d was found to display 23-fold more potent β3-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.

KEYWORDS:

Antagonist; Cancer; Lipolysis and cachexia; β-Adrenergic receptor

PMID:
29574204
DOI:
10.1016/j.ejmech.2018.03.032
[Indexed for MEDLINE]

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