Design, synthesis and biological evaluation of 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one derivatives as potent β2-adrenoceptor agonists

Ce Yi; Gang Xing; Siqi Wang; Xiaoran Li; Yichuang Liu; Jinyan Li; Bin Lin; Anthony Yiu-Ho Woo; Yuyang Zhang; Li Pan; Maosheng Cheng

doi:10.1016/j.bmc.2019.115178

Design, synthesis and biological evaluation of 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one derivatives as potent β₂-adrenoceptor agonists

Bioorg Med Chem. 2020 Jan 1;28(1):115178. doi: 10.1016/j.bmc.2019.115178. Epub 2019 Nov 11.

Authors

Ce Yi¹, Gang Xing¹, Siqi Wang², Xiaoran Li², Yichuang Liu¹, Jinyan Li¹, Bin Lin¹, Anthony Yiu-Ho Woo², Yuyang Zhang², 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: 31753798
DOI: 10.1016/j.bmc.2019.115178

Abstract

A series of β₂-adrenoceptor agonists with an 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one moiety is presented. The stimulatory effects of the compounds on human β₂-adrenoceptor and β₁-adrenoceptor were characterized by a cell-based assay. Their smooth muscle relaxant activities were tested on isolated guinea pig trachea. Most of the compounds were found to be potent and selective agonists of the β₂-adrenoceptor. One of the compounds, (R)-18c, possessed a strong β₂-adrenoceptor agonistic effect with an EC₅₀ value of 24 pM. It produced a full and potent airway smooth muscle relaxant effect same as olodaterol. Its onset of action was 3.5 min and its duration of action was more than 12 h in an in vitro guinea pig trachea model of bronchodilation. These results suggest that (R)-18c is a potential candidate for long-acting β₂-AR agonists.

Keywords: Asthma; COPD; Isoprenaline; Olodaterol; Salmeterol; β(2)-adrenoceptor agonist.

Publication types

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

MeSH terms

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

Substances

Adrenergic beta-Agonists
Benzoxazines
Receptors, Adrenergic, beta-2