J Med Chem. 2020 Feb 27;63(4):1660-1670. doi: 10.1021/acs.jmedchem.9b01831. Epub 2020 Feb 11.
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 . Compound 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 stimulated cholesterol efflux by 53% demonstrating HDL-C functionality.
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。使用小鼠转基因、KO 或功能丧失变异体进行的研究强烈表明，抑制 EL 将导致血浆高密度脂蛋白胆固醇 (HDL-C) 的持续增加，并且可能降低心血管疾病 (CVD) 的风险。在此，我们描述了一系列噁二唑酮的发现，经过优化，确定了化合物 。在小鼠药效学 (PD) 模型中评估了化合物 ，结果显示血浆 HDL-C 增加了 56%。在小鼠胆固醇逆向转运研究中，化合物 刺激胆固醇流出增加了 53%，证明了 HDL-C 的功能。
