Identification of Reversible Small Molecule Inhibitors of Endothelial Lipase (EL) which Demonstrate HDL-C Increase In Vivo

Endothelial lipase (EL) hydrolyzes phospholipids in HDL resulting in reduction in plasma HDL levels. Studies with murine transgenic, KO or loss-of-function variants strongly suggest that inhibition of EL will lead to sustained plasma HDL-C increase and, potentially, a reduced CVD risk. Herein, we describe the discovery of a series of oxadiazole ketones, which upon optimization, led to the identification of Compound 12. Compound 12 was evaluated in a mouse PD model and demonstrated a 56% increase in plasma HDL-C. In a mouse reverse cholesterol transport study, Compound 12 stimulated cholesterol efflux by 53% demonstrating HDL-C functionality.