Although β 2 -agonists are crucial for treatment of chronic respiratory diseases, optimizing β 2 -agonistic activity and selectivity remains essential for achieving favorable therapeutic outcomes. A structure-based molecular design workflow was employed to discover a novel class of β 2 agonists featuring a 5hydroxy-4H-benzo [1,4]oxazin-3-one scaffold, which potently stimulated β 2 adrenoceptors (β 2 -ARs). Screening for the β 2agonistic activity and selectivity led to the identification of compound A19 (EC 50 = 3.7 pM), which functioned as a partial β 2 -agonist in HEK-293 cells containing endogenous β 2 -ARs. Compound A19 exhibited significant relaxant effects, rapid onset time (Ot 50 = 2.14 min), and long duration of action (>12 h) on isolated guinea pig tracheal strips, as well as advantageous pharmacokinetic characteristics in vivo, rendering A19 suitable for inhalation administration. Moreover, A19 suppressed the upregulation of inflammatory cytokines and leukocytes and improved lung function in a rat model of COPD, thereby indicating that A19 is a potential β 2 agonist candidate for further study.