Abstract：
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.
摘要：
尽管β2-激动剂对慢性呼吸系统疾病的治疗至关重要，优化β2-激动活性和选择性对于获得良好的治疗结果仍然至关重要.采用基于结构的分子设计工作流程来发现一类新型的β2激动剂，其特征是5-羟基-4H-苯并[1,4]恶嗪-3-酮支架，能有效刺激β2肾上腺素受体（β2-ARs）。筛选β2-激动活性和选择性导致化合物A19(EC50=3.7pM)的鉴定,在含有内源性β2-ARs的HEK-293细胞中充当部分β2激动剂。化合物A19表现出显著的松弛作用，快速起效时间（Ot50=2.14分钟），对离体豚鼠气管条的作用时间长(>12小时)，以及有利的体内药代动力学特征，使A19适合吸入给药。此外，A19在COPD大鼠模型中抑制炎性细胞因子和白细胞的上调并改善肺功能,从而表明A19是用于进一步研究的潜在β2激动剂候选物。
