Background: Dapagliflozin, developed as an SGLT-2 inhibitor, has a low melting point and high hygroscopicity, which needs extreme care during pharmaceutical production to keep the active pharmacological property. Various attempts have been made to overcome these problematic properties.

Objectives: To develop dapagliflozin prodrugs that have similar pharmacological effects with improved hygroscopicity and thermal stability.

Methods: The novel dapagliflozin ester prodrugs containing pharmaceutically acceptable moieties were synthesized and their pharmacokinetics (PK) and physical properties were compared with dapagliflozin propanediol hydrate (DPD, Farxiga®). The PK in dog and rat, in vitro stability, hygroscopicity, and physical property studies in accelerated conditions (40°C, 75% RH) were performed with prodrugs.

Results and Discussions: Among the eight synthesized prodrugs, Cmax and AUC0-48h values of prodrug 8b (1.35 μg/ml and 14.78 μg·h/ml, respectively) were similar to those of DPD (1.67 μg/ml and 14.27 μg·h/ml, respectively). However, the rest of the prodrugs 8a, 8c, 8d, 8e, 8f, 8g and 8h showed significantly lower Cmax and AUC0-48h values than DPD. Prodrug 8b completely converted into parent drug in the body.

Conclusion: The novel prodrug 8b exhibited comparative PK profile to that of DPD, but with low hygroscopic property and better thermal stability than DPD.

背景：Dapagliflozin作为SGLT-2抑制剂而开发，具有低熔点和高吸湿性，在药物生产过程中需要格外小心以保持活性药理特性。已经进行了各种尝试来克服这些有问题的特性。

目的：开发达格列净前药，这些药具有相似的药理作用，并具有改善的吸湿性和热稳定性。

方法：合成含有药物可接受部分的新型达格列净酯前药，并与达格列净丙二醇水合物（DPD，Farxiga®）比较其药代动力学（PK）和物理性质。用前药在加速条件下（40°C，75％RH）进行了犬和大鼠的PK，体外稳定性，吸湿性和物理性质研究。

结果与讨论：在8种合成前药中，前药8b的Cmax和AUC0-48h值（分别为1.35μg/ ml和14.78μg·h / ml）与DPD相似（1.67μg/ ml和14.27μg·h） / ml）。但是，其余的前药8a，8c，8d，8e，8f，8g和8h的Cmax和AUC0-48h值均明显低于DPD。前药8b在体内完全转化为母体药物。

结论：新型前药8b的PK曲线与DPD相当，但吸湿性低，热稳定性优于DPD。