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

Title

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

Creator

Geldenhuys Werner J; Caporoso Joel; Leeper Thomas C; Lee Yoon-Kwang; Lin Li; Darvesh Altaf S; Sadana Prabodh

Publisher

Bioorganic & medicinal chemistry letters

Date

2017
2017-01

Description

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 10mg/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.

Subject

*Diabetes; *High-fat diet; *Homology modeling; *Hyperlipidemia; *Lipoprotein lipase; *Liver cirrhosis; *Obesity; Animals; Benzeneacetamides/chemical synthesis/chemistry/*pharmacology; Dose-Response Relationship; Drug; Imidazoles/chemical synthesis/chemistry/*pharmacology; Lipoprotein Lipase/*metabolism; Mice; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

303–308

Issue

2

Volume

27

Citation

Geldenhuys Werner J; Caporoso Joel; Leeper Thomas C; Lee Yoon-Kwang; Lin Li; Darvesh Altaf S; Sadana Prabodh, “Structure-activity and in vivo evaluation of a novel lipoprotein lipase (LPL) activator.,” NEOMED Bibliography Database, accessed September 16, 2021, https://neomed.omeka.net/items/show/3503.

Social Bookmarking