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.

中文翻译：

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鉴定可证明HDL-C体内增加的内皮脂肪酶（EL）的可逆小分子抑制剂。

内皮脂肪酶（EL）水解高密度脂蛋白（HDL）中的磷脂，导致血浆HDL水平降低。鼠类转基因，KO或功能丧失型变体的研究强烈表明，抑制EL会导致持续的血浆高密度脂蛋白胆固醇（HDL-C）升高，并有可能降低心血管疾病（CVD）的风险。本文中，我们描述了一系列恶二唑酮的发现，这些恶二唑酮经过优化后可以鉴定化合物12。化合物12在小鼠药效学（PD）模型中进行了评估，并证明血浆HDL-C升高了56％。在一项小鼠胆固醇逆向转运研究中，化合物12刺激胆固醇外流达53％，证明了HDL-C的功能。