title: Structure-activity and in vivo evaluation of a novel lipoprotein lipase (LPL) activator.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV 26505, United States. Electronic address: werner.geldenhuys@hsc.wvu.edu.
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Geldenhuys
authors.affiliation: Department of Chemistry, University of Akron, Akron, OH 44323, United States.
authors.forename: Joel
authors.initials: J
authors.lastname: Caporoso
authors.affiliation: Department of Chemistry, University of Akron, Akron, OH 44323, United States.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Leeper
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, United States.
authors.forename: Yoon-Kwang
authors.initials: YK
authors.lastname: Lee
authors.affiliation: Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, United States.
authors.forename: Altaf S
authors.initials: AS
authors.lastname: Darvesh
authors.affiliation: Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, United States.
authors.forename: Prabodh
authors.initials: P
authors.lastname: Sadana
mesh_terms: D000818:Animals; D044482:Benzeneacetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008071:Lipoprotein Lipase / Q000378:metabolism*; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D044482:Benzeneacetamides; D007093:Imidazoles; D008071:Lipoprotein Lipase
keywords: Diabetes; High-fat diet; Homology modeling; Hyperlipidemia; Lipoprotein lipase; Liver cirrhosis; Obesity