Novel sodium–hydrogen exchanger 1 inhibitors with diphenyl ketone scaffold: Design, Synthesis, mechanism and evaluation in mice model of heart failure

Abstract

Sodium-hydrogen exchanger 1 (NHE1) is a potential target for drug discovery of heart failure (HF). Cardioprotection effect of empagliflozin (EMPA) was reported to be related to binding with NHE1 protein. Herein, a series of NHE1 inhibitors bearing benzhydryl and diphenyl ketone skeleton were rationally designed and efficiently synthesized. Cell viability assay and pH recovery experiment based on H9c2 cells were conducted and compound 7g was found to have equal NHE1 inhibitory activity to cariporide (0.64 μM) with the IC₅₀ values of 0.78 μM. In vitro, 7g at 1 μM effectively rescued glucose deprivation (GD)-induced cellular damage by decreased overload of Ca²⁺ concentration and reactive oxygen species (ROS), improved mitochondrial dysfunction and autophagy. In vivo, compared with the clinically approved drug empagliflozin (30 mg/kg), 7g alleviated left ventricular systolic dysfunction in a heart failure model induced by isoproterenol (ISO) at lower concentration (10 mg/kg). In summary, this study supplies a promising lead compound with novel scaffold for NHE1 inhibitor and also provide a feasible strategy for HF drug discovery.