Design, synthesis and biological evaluation of 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one derivatives as potent β<sub>2</sub>-adrenoceptor agonists.
Yi C, Xing G, Wang S, Li X, Liu Y, Li J, Lin B, Woo AY, Zhang Y, Pan L, Cheng M.
A series of β<sub>2</sub>-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 β<sub>2</sub>-adrenoceptor and β<sub>1</sub>-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 β<sub>2</sub>-adrenoceptor. One of the compounds, (R)-18c, possessed a strong β<sub>2</sub>-adrenoceptor agonistic effect with an EC<sub>50</sub> 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 β<sub>2</sub>-AR agonists.