新型前药类S1P1激动剂Syl978的药理活性  

Pharmacological activity of a novel selective S1P1 agonist (prodrug) Syl978

作　　者：金晶[1] 汪小涧[1] 周琬琪[1] 薛妮娜[1] 尹大力[1] 陈晓光[1] 

机构地区：[1]中国医学科学院北京协和医学院药物研究所,天然药物活性物质与功能国家重点实验室,北京100050

出　　处：《中国药科大学学报》2014年第3期358-361,共4页Journal of China Pharmaceutical University

基　　金：国家自然科学基金资助项目(No.81202545;81102322)~~

摘　　要：通过对新型免疫抑制剂芬戈莫德(FTY720)的结构改造获得具有全新结构的选择性鞘氨醇-1-磷酸1型受体(sphingosine-1-phosphate receptor 1,S1P1)前药类激动剂Syl978。体外S1P受体激动试验表明:其活性磷酸酯形式Syl978-P对S1P1受体具有显著的激动活性,而对于鞘氨醇-1-磷酸3型受体(S1P3)的激动作用较弱,显示良好的受体激动选择性。单次灌胃分别给予SD大鼠0.3,1,3 mg/kg的Syl978都能够显著降低动物外周血淋巴细胞水平,且显示出良好的量效关系。单次灌胃给予SD大鼠10 mg/kg的Syl978对大鼠心率并没有明显影响。研究结果表明,Syl978具有较好的体内外生物活性,具有开发成为治疗自身免疫性疾病药物的良好前景。Sy1978 is a synthesized selective S1P1 （sphingosine-l-phosphate receptor 1 ） agonist which is obtained based on the structural modification of fingolimod （FTY720）. Biological evaluation in vitro indicated that Syl978-P, the active form of Syl978 demonstrated nanomole S1P1 agonist activity with 〉 500 selective over S1P3. In SD rats, oral administration of 0. 3, 1 and 3 mg/kg Sy1978 significantly decrease the peripheral blood lymphocytes （PBL） in a dose-dependent manner. Oral administration of 10 mg/kg Sy1978 had no effect on the heart rate of SD rats. In summary, the above results demonstrated that Sy1978 exhibited great selectivity both in vitro and in vivo study, suggesting the potential therapeutic use in the treatment of autoimmune diseases.

关 键 词：鞘氨醇-1-磷酸1型受体 激动剂 Syl978 芬戈莫德 药理活性 

分 类 号：R965[医药卫生—药理学]