Elevated triglycerides (TG) contribute towards increased risk for cardiovascular disease. Lipoprotein lipase (LPL) is an enzyme that is responsible for the metabolism of core triglycerides of very-low density lipoproteins (VLDL) and chylomicrons in the vasculature. In this study, we explored the structure-activity relationships of our lead compound (C10d) that we have previously identified as an LPL agonist. We found that the cyclopropyl moiety of C10d is not absolutely necessary for LPL activity. Several substitutions were found to result in loss of LPL activity. The compound C10d was also tested in vivo for its lipid lowering activity. Mice were fed a high-fat diet (HFD) for four months, and treated for one week at 10 mg/kg. At this dose, C10d exhibited in vivo biological activity as indicated by lower TG and cholesterol levels as well as reduced body fat content as determined by ECHO-MRI. Furthermore, C10d also reduced the HFD induced fat accumulation in the liver. Our study has provided insights into the structural and functional characteristics of this novel LPL activator.

中文翻译：

---

新型脂蛋白脂肪酶（LPL）激活剂的结构活性和体内评价

甘油三酸酯（TG）升高会增加患心血管疾病的风险。脂蛋白脂肪酶（LPL）是负责脉管系统中极低密度脂蛋白（VLDL）和乳糜微粒核心甘油三酸酯代谢的酶。在这项研究中，我们探索了我们先前鉴定为LPL激动剂的先导化合物（C10d）的构效关系。我们发现C10d的环丙基部分不是LPL活性绝对必需的。发现一些取代导致LPL活性的丧失。还测试了化合物C10d的降脂活性。给小鼠喂食高脂饮食（HFD）四个月，并以10 mg / kg的剂量治疗一周。在这个剂量下 C10d表现出体内生物学活性，如通过较低的TG和胆固醇水平以及通过ECHO-MRI确定的降低的体内脂肪含量所表明。此外，C10d还减少了HFD诱导的肝脏脂肪堆积。我们的研究提供了对这种新型LPL活化剂的结构和功能特性的见解。