3,6-脱水dapagliflozin的设计、合成和降血糖活性研究  

Design,Synthesis and Hypoglycemic Activity of 3,6-Anhydrodapagliflozin

作　　者：汪文锦 王玉丽[2] 刘巍[2] 徐为人[1,2] 汤立达[2] 赵桂龙[2] 

机构地区：[1]天津医科大学药学院,天津300070 [2]天津药物研究院天津市新药设计与发现重点实验室,天津300193

出　　处：《中国药学杂志》2014年第19期1755-1759,共5页Chinese Pharmaceutical Journal

基　　金：国家自然科学基金资助项目(21302141);天津市科技支撑计划重点项目(10ZCKFSH01300);天津市自然科学基金资助项目(14JCQNJC129007)

摘　　要：目的研究3,6-脱水dapagliflozin的降血糖活性,确定SGLT2抑制剂中葡萄糖片段上3,6-脱水的修饰对降血糖活性的影响。方法利用dapagliflozin作为原料制备3,6-脱水dapagliflozin,利用体外抑制hSGLT2和hSGLT1以及大鼠尿糖排泄实验2个模型来评价目标化合物的降血糖活性。结果利用dapagliflozin作为原料经过5步制备了3,6-脱水dapagliflozin,总收率55.8%,使用1H-NMR、13C-NMR、HR-MS和IR进行了全面的结构表征,并利用NOESY进一步确定了其立体构型。活性测试表明,3,6-脱水dapagliflozin具有一定的降血糖活性,但是比dapagliflozin活性弱。结论 SGLT2抑制剂中葡萄糖片段上的3,6-脱水的修饰对活性具有不利的影响。OBJECTIVE To determine the effect of replacement of the glucose moiety by 3,6-anhydroglucose moiety in SGLT2 in- hibitors on the hypoglycemic activity by studying the hypoglycemic activity of 3,6-anhydrodapagliflozin. METHODS Dapagliflozin was used as the starting material to synthesize 3,6-anhydrodapagliflozin. In vitro model of hSGLT2/hSGLT1 inhibition and in vivo ani- mal model of rat urinary glucose excretion（UGE） test were used to evaluate the hypoglyeemic activity of 3,6-anhydrodapagliflozin. RE- SULTS 3,6-Anhydrodapagliflozin was prepared from dapagliflozin in 5 steps with overall yield of 55.8%. The structure was fully characterized with 1H-NMR, 13C-NMR, HR-MS and IR, and the stereochemistry was further studied by NOESY. In vitro and in vivo evaluations found that 3,6-anhydrodapagliflozin was an SGLT2 inhibitor that was much less active than dapagliflozin. CONCLUSION Replacement of the glucose moiety by 3,6-anhydroglucose moiety is detrimental to the hypoglycemie activity of SGLT2 inhibitors.

关 键 词：SGLT2抑制剂 3 6-脱水dapagliflozin 合成 降血糖活性 

分 类 号：R97[医药卫生—药品]