Synthesis, biological evaluation and molecular modeling of 2-amino-2-phenylethanol derivatives as novel β2-adrenoceptor agonists

Xinyue Ge; Yongmei Mo; Gang Xing; Lei Ji; Haiyan Zhao; Jianfang Chen; Bin He; Xuyao Chen; Ruijuan Xing; Xiaoqiang Li; Ying Zhao; Jinyan Li; Haining Yan; Anthony Yiu-Ho Woo; Yuyang Zhang; Bin Lin; Li Pan; Maosheng Cheng

doi:10.1016/j.bioorg.2018.04.017

Synthesis, biological evaluation and molecular modeling of 2-amino-2-phenylethanol derivatives as novel β₂-adrenoceptor agonists

Bioorg Chem. 2018 Sep:79:155-162. doi: 10.1016/j.bioorg.2018.04.017. Epub 2018 Apr 26.

Authors

Xinyue Ge¹, Yongmei Mo¹, Gang Xing¹, Lei Ji¹, Haiyan Zhao¹, Jianfang Chen¹, Bin He¹, Xuyao Chen¹, Ruijuan Xing¹, Xiaoqiang Li¹, Ying Zhao¹, Jinyan Li¹, Haining Yan¹, Anthony Yiu-Ho Woo², Yuyang Zhang², Bin Lin¹, Li Pan³, Maosheng Cheng⁴

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China; Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
² Department of Pharmacology, School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China.
³ Department of Medicinal Chemistry, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China; Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: panli65@aliyun.com.
⁴ Department of Medicinal Chemistry, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China; Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: mscheng@syphu.edu.cn.

PMID: 29751321
DOI: 10.1016/j.bioorg.2018.04.017

Abstract

A novel series of 2-amino-2-phenylethanol derivatives were developed as β₂-adrenoceptor agonists. Among them, 2-amino-3-fluoro-5-(2-hydroxy-1-(isopropylamino)ethyl)benzonitrile (compound 2f) exhibited the highest activity (EC₅₀ = 0.25 nM) in stimulating β₂-adrenoceptor-mediated cellular cAMP production with a 763.6-fold selectivity over the β₁-adrenoceptor. The (S)-isomer of 2f was subsequently found to be 8.5-fold more active than the (R)-isomer. Molecular docking was performed to determine the putative binding modes of this new class of β₂-adrenoceptor agonists. Taken together, these data show that compound 2f is a promising lead compound worthy of further study for the development of β₂-adrenoceptor agonists.

Keywords: Asthma; COPD; β(2)-adrenoceptor agonists.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adrenergic beta-2 Receptor Antagonists / chemical synthesis
Adrenergic beta-2 Receptor Antagonists / chemistry
Adrenergic beta-2 Receptor Antagonists / pharmacokinetics
Adrenergic beta-2 Receptor Antagonists / pharmacology*
Animals
Binding Sites
Bronchodilator Agents / chemical synthesis
Bronchodilator Agents / chemistry
Bronchodilator Agents / pharmacokinetics
Bronchodilator Agents / pharmacology*
Ethanolamines / chemical synthesis
Ethanolamines / chemistry
Ethanolamines / pharmacokinetics
Ethanolamines / pharmacology*
Guinea Pigs
HEK293 Cells
Humans
Hydrogen Bonding
Male
Molecular Docking Simulation
Molecular Structure
Muscle, Smooth / drug effects
Receptors, Adrenergic, beta-2 / chemistry
Stereoisomerism
Structure-Activity Relationship
Trachea / drug effects

Substances

2-amino-2-phenylethanol
Adrenergic beta-2 Receptor Antagonists
Bronchodilator Agents
Ethanolamines
Receptors, Adrenergic, beta-2