基于改善理化性质的选择性S1P1受体激动剂的研究

Sphingosine 1-phosphate receptor 1 (S1P1 receptor) agonist is a hot topic for autoimmune disease treatment. This project is based on the slow metabolism problem of FTY720 during clinical usage. On the basis of our previous researches toward selective S1P1 agents, we launched both receptor and ligand based rational drug discovery strategies to identify new lead compounds of S1P1 agonists. The structural modification is applied individualized by using the "Physicochemical Property Oriented Structure Optimization Strategy". The drug candidates of selective S1P1 receptor agonists with good effects on treatment of autoimmune disease as well as ideal pharmacokinetic properties would be selected by the results of physicochemical and biological evaluation. Meanwhile, the regularity and relationships between the structural features and pharmaceutical, physicochemical, pharmacokinetic properties are also studied.

鞘氨醇-1-磷酸I型受体（S1P1 receptor）激动剂是目前自身免疫性疾病药物的研究热点。本项目针对上市药物FTY720临床应用中出现的代谢缓慢的问题，拟在前期构效关系研究基础上，通过基于受体和基于配体的合理药物设计相结合的方法，获得具有全新结构骨架的S1P1受体激动剂先导化合物。进一步基于改善理化性质进行结构修饰研究，对于不同结构类型的化合物采取有针对性的结构修饰策略，通过分析理化性质和生物活性测试结果，进行逐级递进式的多轮结构优化，获得具有较好的疾病治疗效果和理想的药物代谢性质的选择性S1P1受体激动剂候选药物。同时，探索化合物的结构特征与药理活性、理化性质以及代谢性质之间的内在联系和变化规律。

鞘氨醇-1-磷酸I 型受体（S1P1 receptor）激动剂是目前自身免疫性疾病药物的研究热点。本项目针对上市药物FTY720 临床应用中出现的代谢缓慢的问题。通过基于受体和基于配体的合理药物设计相结合的方法，基于改善理化性质进行结构修饰研究共设计合成具有全新结构骨架的S1P1 受体激动剂100余个，通过分析理化性质和生物活性测试结果获得具有较好的疾病治疗效果和理想的药物代谢性质的选择性S1P1 受体激动剂候选药物2个。同时探索了化合物的结构特征与药理活性、理化性质以及代谢性质之间的内在联系和变化规律。