Synthesis and biological evaluation of β2-adrenoceptor agonists bearing the 2-amino-2-phenylethanol scaffold

Xinyue Ge; Anthony Yiu-Ho Woo; Gang Xing; Yali Lu; Yongmei Mo; Ying Zhao; Yi Lan; Jinyan Li; Haining Yan; Li Pan; Yuyang Zhang; Bin Lin; Maosheng Cheng

doi:10.1016/j.ejmech.2018.04.041

Synthesis and biological evaluation of β₂-adrenoceptor agonists bearing the 2-amino-2-phenylethanol scaffold

Eur J Med Chem. 2018 May 25:152:424-435. doi: 10.1016/j.ejmech.2018.04.041. Epub 2018 Apr 30.

Authors

Xinyue Ge¹, Anthony Yiu-Ho Woo², Gang Xing¹, Yali Lu², Yongmei Mo¹, Ying Zhao¹, Yi Lan², Jinyan Li¹, Haining Yan¹, Li Pan¹, Yuyang Zhang², Bin Lin³, 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: randybinlin@gmail.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: 29751236
DOI: 10.1016/j.ejmech.2018.04.041

Abstract

A new series of β₂-adrenoceptor agonists bearing the 2-amino-2-phenylethanol scaffold was synthesized. Evaluation of the compounds using cell assays and an in vitro guinea pig trachea relaxation assay showed that 8-hydroxy-5-(2-hydroxy-1-((4-hydroxyphenethyl)amino)ethyl)quinolin-2(1H)-one (compound 5j) has the best pharmacological profile among all the evaluated compounds. The (S)-isomer of 5j was subsequently found to be the active enantiomer with a promising EC₅₀ value of 1.26 nM in stimulating β₂-adrenoceptor-mediated cAMP accumulation and a substantially higher selectivity for the β₂ than for the β₁ subtype. The putative binding mode of (S)-5j revealed by molecular docking of the β₂-adrenoceptor resembles that in agonist binding. Taken together, these results showed that compound (S)-5j is a promising compound worthy of further study for the development of β₂-adrenoceptor agonists.

Keywords: Bronchodilators; Indacaterol; Trantinterol; β(2)-Adrenoceptor agonists.

MeSH terms

Adrenergic Agonists / chemical synthesis
Adrenergic Agonists / chemistry
Adrenergic Agonists / pharmacology*
Animals
Caco-2 Cells
Dose-Response Relationship, Drug
Ethanolamines / chemical synthesis
Ethanolamines / chemistry
Ethanolamines / pharmacology*
Guinea Pigs
HEK293 Cells
Humans
Male
Models, Molecular
Molecular Structure
Receptors, Adrenergic, beta-2 / metabolism*
Structure-Activity Relationship
Trachea / drug effects
Trachea / metabolism

Substances

2-amino-2-phenylethanol
Adrenergic Agonists
Ethanolamines
Receptors, Adrenergic, beta-2