Design, synthesis and biological evaluation of 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one derivatives as potent β2-adrenoceptor agonists. Issue 12 (15th June 2019)

• Record Type: Journal Article
• Authors: Xing, Gang; Pan, Li; Yi, Ce; Li, Xiaoran; Ge, Xinyue; Zhao, Ying; Liu, Yichuang; Li, Jinyan; Woo, Anthony; Lin, Bin; Zhang, Yuyang; Cheng, Maosheng
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 12(2019)
• Page Start: 2306
• Page End: 2314
• Publication Date: 2019-06-15
• Subjects: Asthma -- COPD -- β2-Adrenoceptor agonist -- Indacaterol -- Salmeterol -- Trantinterol; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.10.043
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: 9g and (R )-18c exhibited the most potent and higher selective in the series for β2 -adrenoceptor activation. 9g and (R )-18c showed the rapid onset time for 2.3 min and 1.9 min, respectively. The duration of action of9g and(R)-18c were more than 12 h. 9g and(R)-18c were worthy of further investigation as lead compounds for the development of β2 -adrenoceptor agonists. Abstract: A series of novel β2 -adrenoceptor agonists with a 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1 H )-one moiety was designed, synthesized and evaluated for biological activity in human embryonic kidney 293 cells and isolated guinea pig trachea. Compounds9g and(R)-18c exhibited the most excellent β2 -adrenoceptor agonistic effects and high β2 /β1 -selectivity with EC50 values of 36 pM for9g 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.