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

Jiyu Jin; Chunxiao Miao; Zhilong Wang; Wanli Zhang; Xiongwen Zhang; Xin Xie; Wei Lu

doi:10.1016/j.ejmech.2018.03.032

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

Jiyu Jin
, Chunxiao Miao
, Zhilong Wang
, Wanli Zhang
, Xiongwen Zhang
, Xin Xie
, Wei Lu^*

^*Corresponding author for this work

School of Chemistry and Molecular Engineering

East China Normal University
CAS - Shanghai Institute of Materia Medica

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

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.

Original language	English
Pages (from-to)	757-770
Number of pages	14
Journal	European Journal of Medicinal Chemistry
Volume	150
DOIs	https://doi.org/10.1016/j.ejmech.2018.03.032
State	Published - 25 Apr 2018

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Antagonist
Cancer
Lipolysis and cachexia
β-Adrenergic receptor

Access to Document

10.1016/j.ejmech.2018.03.032

Cite this

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title = "Design and synthesis of aryloxypropanolamine as β3-adrenergic receptor antagonist in cancer and lipolysis",

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",

author = "Jiyu Jin and Chunxiao Miao and Zhilong Wang and Wanli Zhang and Xiongwen Zhang and Xin Xie and Wei Lu",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Masson SAS",

year = "2018",

month = apr,

day = "25",

doi = "10.1016/j.ejmech.2018.03.032",

language = "英语",

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T1 - Design and synthesis of aryloxypropanolamine as β3-adrenergic receptor antagonist in cancer and lipolysis

AU - Jin, Jiyu

AU - Miao, Chunxiao

AU - Wang, Zhilong

AU - Zhang, Wanli

AU - Zhang, Xiongwen

AU - Xie, Xin

AU - Lu, Wei

PY - 2018/4/25

Y1 - 2018/4/25

N2 - 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.

AB - 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.

KW - Antagonist

KW - Cancer

KW - Lipolysis and cachexia

KW - β-Adrenergic receptor

UR - https://www.scopus.com/pages/publications/85044166888

U2 - 10.1016/j.ejmech.2018.03.032

DO - 10.1016/j.ejmech.2018.03.032

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