近日，我校制药工程学院程卯生教授团队在β₂受体激动剂研究领域取得最新进展，相关研究成果以题为“Discovery and Identification of Novel 5Hydroxy4Hbenzo[1,4]oxazin-3-one Derivatives as Potent β₂Adrenoceptor Agonists through Structure-Based Design, Synthesis, and Biological Evaluation”发表在药物化学权威期刊《Journal of Medicinal Chemistry》（IF=7.3）上。

慢性阻塞性肺疾病（COPD），亦称慢阻肺，是一种常见的肺部疾病，我国因COPD导致的死亡人数居全球首位，给社会及患者家庭带来了极大的经济和精神负担。吸入性支气管扩张剂β₂受体激动剂是临床上治疗COPD的主要药物。

在致力于开发治疗呼吸系统疾病的药物研究中，程卯生教授及其团队通过合理化药物设计和合成过程，成功开发了一系列含有5-羟基-4H-苯并[1,4]噁嗪-3-酮结构片段的分子。经过活性筛选与结构优化，候选化合物A19展现出明显的β₂受体激动活性（EC₅₀= 3.7 pM）和高的选择性（β₂/β₁> 457）。在豚鼠气管平滑肌的离体实验中，表现出显著的松弛效果（E_max= 142.75 %）、快速发挥作用（Ot₅₀= 2.14min）以及持久的作用时长（DoA > 12 h）。此外，化合物A19显示出吸入式给药的体内药代动力学特性，并能有效地在大鼠COPD模型中抑制炎症细胞及炎症因子的上调，显著改善肺功能。这些结果表明，A19作为一种新型β₂激动剂的候选化合物，具备进一步研究与开发的巨大潜力，为呼吸系统疾病的治疗提供了新的方向。

5-羟基-4H-苯并[1,4]噁嗪-3-酮类β₂受体激动剂的发现及优化过程

本文第一作者为沈阳药科大学邢刚博士，沈阳药科大学程卯生教授、刘洋教授和潘莉副教授为本文的共同通讯作者，生命科学与生物制药学院张予阳教授课题组对文章做出了重要贡献，该课题得到了国家自然科学基金面上项目(81872752)支持。

沈阳药科大学程卯生教授团队长期致力于β₂受体激动剂在治疗哮喘和COPD方面的研究工作。该课题组自七十年代起，开始进行β₂受体激动剂的研究，其间完成了多种β₂受体激动剂，例如：喘通、喘舒、马布特罗、福莫特罗、茚达特罗、奥达特罗等品种的合成与开发，同时合成了大量新结构化合物并进行活性研究。其中，首次报道的原创候选药物川丁特罗，属国家1.1类新药，目前已完成Ⅲ期临床研究；盐酸马布特罗研制被列为国家高技术研究发展计划（863计划）课题；盐酸川丁特罗的研究与开发得到科技部“十一五”、“十二五”和“十三五”重大新药创制专项的支持，被列为“十一五”863计划生物和医药技术领域针对重大疾病的药物分子设计及产品开发重点项目，并多次获得国家省部科研项目的资助。相关研究成果已经发表在Journal of Medicinal Chemistry，European Journal of Medicinal Chemistry，Bioorganic Chemistry，Bioorganic&Medicinal Chemistry，Clinical Therapeutics等期刊。

取得上述重要研究进展是课题组全体成员不懈努力的结果，展现出我校在β₂受体激动剂研究领域的重要地位。

课题组近期发表的相关学术文章：

1.Gang Xing,ZhenliLi,Zhengxing Zhi, Ce Yi,Ruiwen Zhang,Huali Yang,Yuyang Zhang,Bin Lin,Yang Liu*,Li Pan*,Maosheng Cheng*. Discovery andidentification of novel 5-hydroxy-4H-benzo[1,4]oxazin-3-one derivatives as potent β₂-adrenoceptor agonists through structure-based design, synthesis, and biological evaluation.J Med Chem. 2024; 67: 2986-3003.

2.Gang Xing, Dahong Li, Anthony Yiu-Ho Woo, Zhengxing Zhi, Lei Ji, Ruijuan Xing, Hailiang Lv, Bin He, Hui An, Haiyan Zhao, Bin Lin, Li Pan*, Maosheng Cheng*. Discovery of a highly selective β₂-adrenoceptor agonist with a 2-amino-2-phenylethanol scaffold as an oral antiasthmatic agent.J Med Chem. 2022; 65: 5514-5527.

3.Gang Xing, Zhengxing Zhi, Ce Yi, Jitian Zou, Xuefeng Jing, Anthony Yiu-Ho Woo, Bin Lin, Li Pan*, Yuyang Zhang*, Maosheng Cheng*. 8-Hydroxyquinolin-2(1H)-one analogues as potentialβ₂-agonists: Design, synthesis and activity study.Eur J Med Chem. 2021;224:113697.

4.Gang Xing, Ce Yi, Peiyuan Dou, Zhengxing Zhi, Bin Lin*, Maosheng Cheng*. Recent progress in the development ofβ₂adrenergic receptor agonists: a patent review (2015-2020).Expert Opin Ther Pat. 2021;31:239-246.

5.Gang Xing,Anthony Yiu-Ho Woo*,Li Pan; Bin Lin,Maosheng Cheng*.Recent Advances inβ₂-Agonists for Treatment of Chronic Respiratory Diseases and Heart Failure.J Med Chem.2020;63: 15218-15242.

6.Ce Yi, Gang Xing, Siqi Wang, Xiaoran Li, Yichuang Liu, Jinyan Li, Bin Lin, Anthony Yiu-Ho Woo, Yuyang Zhang, Li Pan*, Maosheng Cheng*. Design, synthesis and biological evaluation of 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one derivatives as potentβ₂-adrenoceptor agonists.Bioorg Med Chem. 2020; 28: 115178.

7.Gang Xing, Li Pan, Ce Yi, Xiaoran Li, Xinyue Ge, Ying Zhao, Yichuang Liu, Jinyan Li, Anthony Woo, Bin Lin, Yuyang Zhang*, Maosheng Cheng*. Design, synthesis and biological evaluation of 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one derivatives as potentβ₂-adrenoceptor agonists.Bioorg Med Chem. 2019; 27: 2306-2314.

8.Xinyue Ge, Anthony Yiu-Ho Woo, Gang Xing, Yali Lu, Yongmei Mo, Ying Zhao, Yi Lan, Jinyan Li, Haining Yan, Li Pan, Yuyang Zhang, Bin Lin*, Maosheng Cheng*. Synthesis and biological evaluation ofβ₂-adrenoceptor agonists bearing the 2-amino-2-phenylethanol scaffold.Eur J Med Chem. 2018; 152: 424-435.

9.Xinyue Ge, Yongmei Mo, Gang Xing, Lei Ji, Haiyan Zhao, Jianfang Chen, Bin He, Xuyao Chen, Ruijuan Xing, Xiaoqiang Li, Ying Zhao, Jinyan Li, Haining Yan, Anthony Yiu-Ho Woo, Yuyang Zhang, Bin Lin, Li Pan*, Maosheng Cheng*. Synthesis, biological evaluation and molecular modeling of 2-amino-2-phenylethanol derivatives as novelβ₂-adrenoceptor agonists.Bioorg Chem. 2018; 79: 155-162.

10.Anthony Yiu-Ho Woo, Xin-Yue Ge, Li Pan, Gang Xing, Yong-Mei Mo, Rui-Juan Xing, Xiao-Ran Li, Yu-Yang Zhang, Irving W Wainer, Maosheng Cheng*, Rui-Ping Xiao*. Discovery of β-arrestin-biased β₂-adrenoceptor agonists from 2-amino-2-phenylethanol derivatives.Acta Pharmacol Sin. 2019; 40: 1095-1105.