Structural repurposing of SGLT2 inhibitor empagliflozin for strengthening anti-heart failure activity with lower glycosuria.
10.1016/j.apsb.2022.08.023
- Author:
Yixiang XU
1
;
Chao ZHANG
1
;
Kai JIANG
2
;
Xinchun YANG
3
;
Feng CHEN
2
;
Zhiyang CHENG
2
;
Jinlong ZHAO
3
;
Jiaxing CHENG
3
;
Xiaokang LI
1
;
Xin CHEN
1
;
Luoyifan ZHOU
1
;
Hao DUAN
1
;
Yunyuan HUANG
4
;
Yaozu XIANG
2
;
Jian LI
1
Author Information
1. State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
2. Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
3. East China University of Science and Technology-Tengbai Pharmaceutical Innovative Drugs Joint Research Institute, Zhuhai Tengbai Pharmaceutical Co., Ltd., Zhuhai 519000, China.
4. Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, China.
- Publication Type:Journal Article
- Keywords:
Empagliflozin;
Heart failure;
NHE1 (sodium-hydrogen exchanger 1);
SGLT2 inhibitor;
Structural repurposing
- From:
Acta Pharmaceutica Sinica B
2023;13(4):1671-1685
- CountryChina
- Language:English
-
Abstract:
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been reapproved for heart failure (HF) therapy in patients with and without diabetes. However, the initial glucose-lowering indication of SGLT2i has impeded their uses in cardiovascular clinical practice. A challenge of SGLT2i then becomes how to separate their anti-HF activity from glucose-lowering side-effect. To address this issue, we conducted structural repurposing of EMPA, a representative SGLT2 inhibitor, to strengthen anti-HF activity and reduce the SGLT2-inhibitory activity according to structural basis of inhibition of SGLT2. Compared to EMPA, the optimal derivative JX01, which was produced by methylation of C2-OH of the glucose ring, exhibited weaker SGLT2-inhibitory activity (IC50 > 100 nmol/L), and lower glycosuria and glucose-lowering side-effect, better NHE1-inhibitory activity and cardioprotective effect in HF mice. Furthermore, JX01 showed good safety profiles in respect of single-dose/repeat-dose toxicity and hERG activity, and good pharmacokinetic properties in both mouse and rat species. Collectively, the present study provided a paradigm of drug repurposing to discover novel anti-HF drugs, and indirectly demonstrated that SGLT2-independent molecular mechanisms play an important role in cardioprotective effects of SGLT2 inhibitors.
