A thiocarbamate inhibitor of endothelial lipase raises HDL cholesterol levels in mice

M N Greco; M A Connelly; G C Leo; M W Olson; E Powell; Z Huang; M Hawkins; C Smith; C Schalk-Hihi; A L Darrow; H Xin; W Lang; B P Damiano; D J Hlasta

doi:10.1016/j.bmcl.2013.02.113

A thiocarbamate inhibitor of endothelial lipase raises HDL cholesterol levels in mice

Bioorg Med Chem Lett. 2013 May 1;23(9):2595-7. doi: 10.1016/j.bmcl.2013.02.113. Epub 2013 Mar 7.

Authors

M N Greco¹, M A Connelly, G C Leo, M W Olson, E Powell, Z Huang, M Hawkins, C Smith, C Schalk-Hihi, A L Darrow, H Xin, W Lang, B P Damiano, D J Hlasta

Affiliation

¹ Janssen Research and Development, LLC, Welsh and McKean Roads, PO Box 776, Spring House, PA 19477, USA. grecom97@gmail.com

PMID: 23528297
DOI: 10.1016/j.bmcl.2013.02.113

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.

MeSH terms

Animals
Cholesterol, HDL / blood*
Endothelium, Vascular / drug effects
Endothelium, Vascular / enzymology*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology
Hydrogen-Ion Concentration
Lipase / antagonists & inhibitors*
Lipase / metabolism
Lipoproteins, HDL / deficiency
Lipoproteins, HDL / genetics
Lipoproteins, HDL / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Thiocarbamates / chemical synthesis
Thiocarbamates / chemistry*
Thiocarbamates / pharmacology

Substances

Cholesterol, HDL
Enzyme Inhibitors
Lipoproteins, HDL
Thiocarbamates
Lipase