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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 study the hypoglycemic activity of 3,6-anhydro dapagliflozin and to determine the effect of 3,6-dehydration on the hypoglycemic activity of glucose fragments in SGLT2 inhibitors. Methods 3,6-anhydro dapagliflozin was prepared by dapagliflozin as the raw material. The hypoglycemic activity of the target compound was evaluated by in vitro inhibition of hSGLT2 and hSGLT1 and two models of rat urine glucose excretion. Results 3,6-anhydro dapagliflozin was prepared using dapagliflozin as the starting material in 5 steps. The overall yield was 55.8%. The overall structure was characterized by 1H-NMR, 13C-NMR, HR-MS and IR. Its three-dimensional configuration. Activity tests showed that 3,6-anhydro dapagliflozin has some hypoglycemic activity, but weaker than dapagliflozin. Conclusion The 3,6-anhydro modification on glucose fragments in SGLT2 inhibitors has a negative effect on the activity.