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

作　　者：Yixiang Xu Chao Zhang Kai Jiang Xinchun Yang Feng Chen Zhiyang Cheng Jinlong Zhao Jiaxing Cheng Xiaokang Li Xin Chen Luoyifan Zhou Hao Duan Yunyuan Huang Yaozu Xiang Jian Li 

机构地区：[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 [5]Yunnan Key Laboratory of Screening and Research on Anti-pathogenic Plant Resources from West Yunnan,College of Pharmacy,Dali University,Dali 671000,China [6]Clinical Medicine Scientific and Technical Innovation Center,Shanghai Tenth People's Hospital,Tongji University School of Medicine,Shanghai 200092,China [7]Key Laboratory of Tropical Biological Resources of Ministry of Education,College of Pharmacy,Hainan University,Haikou 570228,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第4期1671-1685,共15页药学学报（英文版）

基　　金：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);the Chinese Special Fund for State Key Laboratory of Bioreactor Engineering(2060204)。

摘　　要：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(IC_(50)>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.

关 键 词：Heart failure SGLT2 inhibitor Empagliflozin Structural repurposing NHE1(sodium-hydrogen exchanger 1) 

分 类 号：R914[医药卫生—药物化学] R96[医药卫生—药学]