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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Synthesis and Evaluation of Dapagliflozin Ester Prodrugs with Improved Hygroscopicity and Thermal Stability

Author(s): Si Young Sung, Yu Na Chae, Dae Young Lee, Kyeong Min Kim, Eun Jung Kim, Ji Hye Han, Wook Kim and Sung-Hwa Yoon*

Volume 17, Issue 11, 2020

Page: [1409 - 1421] Pages: 13

DOI: 10.2174/1570180817999200618162949

Price: $65

Abstract

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.

Keywords: Prodrug, dapagliflozin, Farxiga®, SGLT-2 inhibitor, thermal stability, diabetes.

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