Structure-activity and in vivo evaluation of a novel lipoprotein lipase (LPL) activator

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• 作者：Werner J. Geldenhuys^a ; ^{werner.geldenhuys@hsc.wvu.edu} ; Joel Caporoso^b ; Thomas C. Leeper^b ; Yoon-Kwang Lee^c ; Li Lin^d ; Altaf S. Darvesh^d ; Prabodh Sadana^d ;
• 关键词：Lipoprotein lipase ; Homology modeling ; Hyperlipidemia ; High-fat diet ; Liver cirrhosis ; Obesity ; Diabetes
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：27
• 期：2
• 页码：303-308
• 全文大小：1636 K
• 卷排序：27

文摘

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.