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

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

Authors

Jiyu Jin¹, Chunxiao Miao², Zhilong Wang³, Wanli Zhang², Xiongwen Zhang⁴, Xin Xie⁵, Wei Lu⁶

Affiliations

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.

PMID: 29574204
DOI: 10.1016/j.ejmech.2018.03.032

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.

MeSH terms

3T3-L1 Cells
Adipose Tissue / drug effects
Adipose Tissue / metabolism
Adrenergic Antagonists / chemical synthesis
Adrenergic Antagonists / chemistry
Adrenergic Antagonists / pharmacology*
Animals
Cell Proliferation / drug effects
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Lipolysis / drug effects*
Male
Mice
Mice, Inbred BALB C
Molecular Structure
Neoplasms / drug therapy*
Neoplasms / metabolism
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Propanolamines / chemical synthesis
Propanolamines / chemistry
Propanolamines / pharmacology*
Receptors, Adrenergic, beta-3 / metabolism*
Structure-Activity Relationship

Substances

Adrenergic Antagonists
Propanolamines
Receptors, Adrenergic, beta-3
oxypropanolamine