化学
兴奋剂
药理学
立体化学
EC50型
离体
受体
部分激动剂
体外
生物化学
医学
作者
Gang Xing,Zhenli Li,Zhengxing Zhi,Ce Yi,Ruiwen Zhang,Huali Yang,Yuyang Zhang,Bin Lin,Yang Liu,Pan Li,Maosheng Cheng
标识
DOI:10.1021/acs.jmedchem.3c02074
摘要
Although β2-agonists are crucial for treatment of chronic respiratory diseases, optimizing β2-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 β2 agonists featuring a 5-hydroxy-4H-benzo[1,4]oxazin-3-one scaffold, which potently stimulated β2 adrenoceptors (β2-ARs). Screening for the β2-agonistic activity and selectivity led to the identification of compound A19 (EC50 = 3.7 pM), which functioned as a partial β2-agonist in HEK-293 cells containing endogenous β2-ARs. Compound A19 exhibited significant relaxant effects, rapid onset time (Ot50 = 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 β2 agonist candidate for further study.
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