急性肺损伤是一种严重的急性肺部炎症综合症，临床缺乏治疗药物。而五环三萜衍生物CDDO-Me含有关键药效团α-氰基-α,β-不饱和酮，具有强效抗炎活性。但是该关键药效团选择性不足，限制了其进一步临床开发。本项目针对急性肺损伤病理过程中高表达的ROS的特点，从关键药效团α-氰基-α,β-不饱和酮的靶向ROS前药修饰入手，发现活性和安全性兼顾的新型衍生物。我们采用1,4-加成物捕捉和释放技术，实现对强迈克尔受体α-氰基-α,β-不饱和酮的前药修饰；使用活性氧选择性响应的芳基硼酸酯基团，实现病理微环境的选择性活化；通过前药部分的构效关系研究，实现前药稳定性和选择性释放的有效平衡。通过该研究一方面可为急性肺损伤提供活性和安全性兼顾的药物；另一方面也为针对强迈克尔受体的前药研究提供了新策略。

Acute lung injury is a medical condition occurring in critically ill patients characterized by widespread inflammation in the lungs, which is lack of effective drugs. CDDO-Me, a synthetic analog of pentacyclic triterpene, is a potent anti-inflammatory drug with key pharmacophore of α-cyano-α,β-unsaturated ketone. However, this pharmacophore is lack of selectivity, limiting the further clinical development. In this project, we plan to develop targeting prodrug of CDDO-Me on the key pharmacophore, which can release the drug under the high ROS level. The 1,4-additive releasing and trapping technique will be developed to design the prodrugs and the aryl borate ester will be used to response to the ROS. We will further carry out the SAR study to balance the stability and the releasing characters of the prodrug. This study not only can result in new effective medicines for the treatment of ALI, but also provide a new strategy for developing prodrugs of α-cyano-α,β-unsaturated ketone.