达格列净芳环间亚甲基改造对活性和药代性质的影响

目的：考察达格列净芳环间亚甲基的取代对活性和药代性质的影响，为寻找更理想的药物探索改造方向。方法：考察取代衍生物对正常大鼠糖负荷后的尿排糖量、血糖和尿量等指标，aY--常大鼠体内静脉给药和经口给药后的血药浓度，并计算药代参数。结果：（1）大鼠尿排糖和降血糖实验显示，与模型组相比，一甲基取代产物（TY702—5）和二甲基取代产物（TY702—5D）在0-6h和6～24h尿排糖量及O～3h血糖抑制率呈剂量依赖性增加（P〈0．05）；同等剂量下，TY702—5和TY702—5D在0～6h和6．24h尿排糖量及0-3h血糖抑制率明显低于达格列净组（尸〈0．05）；同等剂量的TY702—5D的血糖抑制效果优于尿排糖效果。（2）体内吸收实验显示，与达格列净相比，TY702—5的吸收速度（Tmax）和程度（Cmax和AUC）增加，消除半衰期（T1/2）基本不变，组织分布和生物利用度下降。TY702—5D的药物吸收速度加快，吸收程度降低，组织分布增加，消除半衰期和生物利用度下降。结论：达格列净芳环问亚甲基改造后，药物的活性降低，且对尿糖和血糖的影响存在差异，对药物的各项药代参数有较大影响，提示利用这个位置结合其他部位进行改造，有可能得到一个更理想药物。

Effect of methylene transformation between aromatic rings in dapagliflozin on pharmacokinetics and its active properties

Objective： To observe the effect on pharmacokinetics and active properties by transforming methylene between aromatic rings in FORXIGA, and search for better drugs to explore the direction of transformation. Methods： Substituted derivatives were observed in normal rats about urine glucose excretion test, blood glucose and urine volume and other indicators, as well as the plasma concentration after intravenous administration and oral administration,based on which pharmacokinetic parameters were calculated. Results： （1）The urine glucose excretion and blood glucose test in rats displayed that compared with the model group, the urine glucose excretion during 0-6 h and 6-24 h and blood glucose inhibition rates during 0-3 h of one methyl-substituted product （TY702-5） group and dimethyl substituted product （TY702-5D） group were increased at a dose-dependence （P〈0.05）; under the same dosage, the urine glucose excretion during 0-6 h and 6-24 h and blood sugar inhibition rates during 0-3 h of TY702-5 group and TY702-JD group were significantly lower than those of dapagliflozin group （P〈0.05）; under the same dosage, the blood sugar inhibition rates of TY702-5D group was better than the urine glucose excretion. （2）The absorption test in rats displayed that compared with dapagliflozin, the rate of absorption （Tmax） and extent （Cmax and AUC） for TY702-5 were increased whereas elimination half-life （Tin） maintained constant and tissue distribution and bioavailability were decreased. Furthermore, the rate of absorption and extent for TYT02-5D were decreased and tissue distribution increased while elimination half-life and bioavailability were decreased. Conclusion： The methylene transformation between the aromatic ring of dapagliflozin can reduce the activity of the drug, and significant differences are found in its effects on urine glucose and blood glucose. And also has a greater impact on the pharmacokinetic parameters of the drug, indicating that a better drug can be acquired through the combination of this position and other parts of the transformation.