Discovery and Identification of Novel 5-Hydroxy-4-benzo[1,4]oxazin-3-one Derivatives as Potent β-Adrenoceptor Agonists through Structure-Based Design, Synthesis, and Biological Evaluation.

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