文献类型：期刊文献

英文题名：Structural repurposing of SGLT2 inhibitor empagliflozin for strengthening anti-heart failure activity with lower glycosuria

作者：Xu, Yixiang[1];Zhang, Chao[1];Jiang, Kai[2];Yang, Xinchun[3];Chen, Feng[2];Cheng, Zhiyang[2];Zhao, Jinlong[3];Cheng, Jiaxing[3];Li, Xiaokang[1];Chen, Xin[1];Zhou, Luoyifan[1];Duan, Hao[1];Huang, Yunyuan[4];Xiang, Yaozu[2];Li, Jian[1,5,6,7]

机构：[1]East China Univ Sci & Technol, Shanghai Frontiers Sci Ctr Optogenet Tech Cell Met, Frontiers Sci Ctr Materiobiol & Dynam Chem, Sch Pharm,Shanghai Key Laboratoryof New Drug Desig, Shanghai 200237, Peoples R China;[2]Tongji Univ, Shanghai East Hosp, Sch Life Sci & Technol, Shanghai 200092, Peoples R China;[3]East China Univ Sci & Technol, Zhuhai Tengbai Pharmaceut Co Ltd, Tengbai Pharmaceut Innovat Drugs Joint Res Inst, Zhuhai 519000, Peoples R China;[4]Cent China Normal Univ, Sch Life Sci, Hubei Key Lab Genet Regulat & Integrat Biol, Wuhan 430079, Peoples R China;[5]Dali Univ, Coll Pharm, Yunnan Key Lab Screening & Res Antipathogen Plant, Dali 671000, Peoples R China;[6]Tongji Univ Sch Med, Shanghai Peoples Hosp 10, Clin Med Sci & Tech Innovat Ctr, Shanghai 200092, Peoples R China;[7]Hainan Univ, Coll Pharm, Key Lab Trop Biol Resources, Minist Educ, Haikou 570228, Peoples R China

年份：2023

卷号：13

期号：4

起止页码：1671

外文期刊名：ACTA PHARMACEUTICA SINICA B

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000985862200001)】；

基金：This work was supported by the National key R & D Program of China (2021YFA0804904), the National Natural Science Foundation of China (22107030), the Chinese Postdoctoral Science Foundation (2020M681211), the Shanghai Morning Light Program (20CG36, China), the Shanghai Frontier Science Center of Optogenetic Techniques for Cell Metabolism (2021 Sci & Tech 03-28, China), the Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZDCX20212702, China), and the Chinese Special Fund for State Key Laboratory of Bioreactor Engineering (2060204).

语种：英文

摘要：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.