Abstract
By screening directed libraries of serine hydrolase inhibitors using the cell surface form of endothelial lipase (EL), we identified a series of carbamate-derived (EL) inhibitors. Compound 3 raised plasma HDL-C levels in the mouse, and a correlation was found between HDL-C and plasma compound levels. Spectroscopic and kinetic studies support a covalent mechanism of inhibition. Our findings represent the first report of EL inhibition as an effective means for increasing HDL-C in an in vivo model.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Cholesterol, HDL / blood*
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / enzymology*
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology
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Hydrogen-Ion Concentration
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Lipase / antagonists & inhibitors*
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Lipase / metabolism
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Lipoproteins, HDL / deficiency
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Lipoproteins, HDL / genetics
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Lipoproteins, HDL / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Thiocarbamates / chemical synthesis
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Thiocarbamates / chemistry*
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Thiocarbamates / pharmacology
Substances
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Cholesterol, HDL
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Enzyme Inhibitors
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Lipoproteins, HDL
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Thiocarbamates
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Lipase