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。
Abstract
OBJECTIVE To determine the effect of replacement of the glucose moiety by 3,6-anhydroglucose moiety in SGLT2 inhibitors 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 animal model of rat urinary glucose excretion(UGE) test were used to evaluate the hypoglycemic activity of 3,6-anhydrodapagliflozin. RESULTS 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. CONCULSION Replacement of the glucose moiety by 3,6-anhydroglucose moiety is detrimental to the hypoglycemic activity of SGLT2 inhibitors.
关键词
SGLT2抑制剂 /
3 /
6-脱水dapagliflozin /
合成 /
降血糖活性
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Key words
SGLT 2 inhibitor /
3,6-anhydrodapagliflozin /
synthesis /
hypoglycemic activity
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中图分类号：
R97
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参考文献
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脚注
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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)
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