Why the study?
Endothelial lipase reduces plasma HDL levels, and genetic studies suggest its inhibition could lead to sustained plasma HDL-C increases and potentially reduced cardiovascular disease risk.
Does compound 12 increase plasma HDL-C and stimulate cholesterol efflux in mouse models?
Does compound 12 increase plasma HDL-C and stimulate cholesterol efflux in mouse models?
Compound 12, a novel endothelial lipase inhibitor, significantly increases plasma HDL-C and stimulates cholesterol efflux in mouse models, suggesting potential for cardiovascular disease risk reduction.
Endothelial lipase (EL) hydrolyzes phospholipids in high-density lipoprotein (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 high-density lipoprotein cholesterol (HDL-C) increase and, potentially, a reduced cardiovascular disease (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 pharmacodynamics (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.
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Tora et al. (2020) studied this question.
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