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. Issue 1 (1st January 2020)

• Record Type: Journal Article
• Authors: Yi, Ce; Xing, Gang; Wang, Siqi; Li, Xiaoran; Liu, Yichuang; Li, Jinyan; Lin, Bin; Woo, Anthony Yiu-Ho; Zhang, Yuyang; Pan, Li; Cheng, Maosheng
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 1(2020)
• Publication Date: 2020-01-01
• Subjects: Asthma -- COPD -- β2-adrenoceptor agonist -- Isoprenaline -- Salmeterol -- Olodaterol; 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.2019.115178
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: (R )-18a (R)-18c and (R )-18f exhibited the most potent with EC50 values of 9.1 pM 24 pM and 16 pM, respectively. (R)-18c were worthy of further investigation as a lead compound for the development of β2 -adrenoceptor agonists. Abstract: A series of β2 -adrenoceptor agonists with an 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1, 4-benzoxazine-3(4 H )-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.