前体药物（前药）的酯键修饰可有效改善活性药物体内系统暴露水平，但系统暴露与靶点暴露间关系未见改善或难以定论。依照前药激活部位不同的前药新分类标准，上市前药仍需进行再评价。申请者总结了最新相关研究，发现多数酯类前药属性与人体羧酸酯类水解酶（CEH）的催化作用相关，CEH作用属性、组织分布等特征是影响该类前药靶向性与最终命运的关键，继而影响前药研发和安全用药。基于本领域中已积累的坚实工作基础（包括已建立的前药代谢酶表型与底物归属筛选与因果关系验证体系，自我设计开发的多种与CEH家族及亚型相互作用配体探针与分子工具），申请人拟以临床中现存挑战性的五种代表性前药为研究对象，开展六种人源性CEH与上述前药间的酶表型归属关系研究，建立上述代谢酶与五种前体药物的对应及构效关系，评价前药体内激活部位及其相关属性，为完善前药分类新标准、实现前药优化有效性、提升临床药物安全用药水平等奠定科学基础。

The esterification strategy in prodrug can be used to improve the systemic exposure of the active drugs. However, it is still unclear what ADME properties is most favorable for the target delivery to the action site and its related pharmacological outcomes, because the prodrugs is activated in the different sites of human body. Here, the applicant has made a summary of the latest related studies: the characteristics of human ester hydrolases, including catalysis mechanisms, tissue distribution and ligand-substrate specificities, will significantly affect the prodrugs targeting as well as post-targeting effects. This is closely related to the field of new drug discovery and development, including drug safety use. Meanwhile, the applicant has established the screening method of drug-metabolizing enzyme phenotypes and specific substrates as well as the proving systems of causal relationship, and developed the ligand probes and molecular tools for their interactions with carboxylic ester hydrolases（CEH） subfamilies and subtypes. Based on the preliminary works, five typical prodrugs which are encountering a challenge in the clinic will be taken as an example to re-evaluate their attributions and structure-activity relationships with six human CEHs. The results of this project will prompt prodrug classification criteria, effectiveness of prodrugs modification and clinical rational drug use.