Design, synthesis and biological evaluation of 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one derivatives as potent β2-adrenoceptor agonists

Gang Xing; Li Pan; Ce Yi; Xiaoran Li; Xinyue Ge; Ying Zhao; Yichuang Liu; Jinyan Li; Anthony Woo; Bin Lin; Yuyang Zhang; Maosheng Cheng

doi:10.1016/j.bmc.2018.10.043

Design, synthesis and biological evaluation of 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one derivatives as potent β₂-adrenoceptor agonists

Bioorg Med Chem. 2019 Jun 15;27(12):2306-2314. doi: 10.1016/j.bmc.2018.10.043. Epub 2018 Nov 1.

Authors

Gang Xing¹, Li Pan¹, Ce Yi¹, Xiaoran Li², Xinyue Ge¹, Ying Zhao¹, Yichuang Liu¹, Jinyan Li¹, Anthony Woo², Bin Lin¹, Yuyang Zhang³, 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 Pharmacology, School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: 13614053862@163.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: 30392952
DOI: 10.1016/j.bmc.2018.10.043

Abstract

A series of novel β₂-adrenoceptor agonists with a 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one moiety was designed, synthesized and evaluated for biological activity in human embryonic kidney 293 cells and isolated guinea pig trachea. Compounds 9g and (R)-18c exhibited the most excellent β₂-adrenoceptor agonistic effects and high β₂/β₁-selectivity with EC₅₀ values of 36 pM for 9g and 21 pM for (R)-18c. They produced potent airway smooth muscle relaxant effects with fast onset of action and long duration of action in an in vitro guinea pig trachea model of bronchodilation. These results support further development of the two compounds into drug candidates.

Keywords: Asthma; COPD; Indacaterol; Salmeterol; Trantinterol; β(2)-Adrenoceptor agonist.

Publication types

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

MeSH terms

Adrenergic beta-2 Receptor Agonists / chemical synthesis
Adrenergic beta-2 Receptor Agonists / metabolism
Adrenergic beta-2 Receptor Agonists / pharmacology*
Animals
Binding Sites
Bronchodilator Agents / chemical synthesis
Bronchodilator Agents / metabolism
Bronchodilator Agents / pharmacology*
Drug Design
Ethanolamines / chemical synthesis
Ethanolamines / metabolism
Ethanolamines / pharmacology*
Guinea Pigs
HEK293 Cells
Humans
Hydroxyquinolines / chemical synthesis
Hydroxyquinolines / metabolism
Hydroxyquinolines / pharmacology*
Male
Molecular Docking Simulation
Receptors, Adrenergic, beta-2 / chemistry
Receptors, Adrenergic, beta-2 / metabolism
Trachea / drug effects

Substances

Adrenergic beta-2 Receptor Agonists
Bronchodilator Agents
Ethanolamines
Hydroxyquinolines
Receptors, Adrenergic, beta-2