Cariporide mesilate

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.

Large clinical trials recently showed that sodium-glucose cotransporter 2 (SGLT2) inhibitors improve the prognosis of heart failure patients with or without diabetes. Using a mouse model of large myocardial infarction, we investigated the therapeutic effects and underlying molecular mechanisms of the highly selective SGLT2 inhibitor empagliflozin in heart failure. Four weeks after myocardial infarction induced by left coronary artery ligation, the surviving mice were assigned to vehicle or empagliflozin groups and treated for 8 weeks. Empagliflozin did not alter body weight, blood pressure, glycohemoglobin, blood glucose or beta-hydroxybutyrate levels but significantly attenuated cardiac dysfunction and left ventricular dilatation (remodeling). Hearts from empagliflozin-treated mice showed less fibrosis, less cardiomyocyte hypertrophy, and lower myocardial ANP levels than those from vehicle-treated mice. Autophagy was augmented in cardiomyocytes from empagliflozin-treated mice, as indicated by increased myocardial microtubule-associated protein-1 LC3 (light chain 3)-II levels and LC-3-II/I ratio as well as increased levels of cathepsin D and ATP. Additionally, numerous autophagic vacuoles and lysosomes were observed, accompanied by increased AMP-activated protein kinase (AMPK) phosphorylation and suppression of mammalian target of rapamycin phosphorylation. Myocardial sodium-hydrogen antiporter (NHE)-1 expression was increased in infarcted mice, and that effect was unchanged by empagliflozin. In vitro, empagliflozin increased autophagic flux and induced an intracellular pH drop, AMPK activation and ATP production in cardiomyocytes. These effects were similar to those of the NHE-1 inhibitor cariporide, suggesting a possibility that they both act on the same pathway. Empagliflozin is a beneficial pharmacological tool that enhances autophagy to reverse remodeling in the postinfarction heart.