title: A thiocarbamate inhibitor of endothelial lipase raises HDL cholesterol levels in mice.
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.
authors.affiliation: Janssen Research and Development, LLC, Welsh and McKean Roads, PO Box 776, Spring House, PA 19477, USA. grecom97@gmail.com
authors.forename: M N
authors.initials: MN
authors.lastname: Greco
authors.forename: M A
authors.initials: MA
authors.lastname: Connelly
authors.forename: G C
authors.initials: GC
authors.lastname: Leo
authors.forename: M W
authors.initials: MW
authors.lastname: Olson
authors.forename: E
authors.initials: E
authors.lastname: Powell
authors.forename: Z
authors.initials: Z
authors.lastname: Huang
authors.forename: M
authors.initials: M
authors.lastname: Hawkins
authors.forename: C
authors.initials: C
authors.lastname: Smith
authors.forename: C
authors.initials: C
authors.lastname: Schalk-Hihi
authors.forename: A L
authors.initials: AL
authors.lastname: Darrow
authors.forename: H
authors.initials: H
authors.lastname: Xin
authors.forename: W
authors.initials: W
authors.lastname: Lang
authors.forename: B P
authors.initials: BP
authors.lastname: Damiano
authors.forename: D J
authors.initials: DJ
authors.lastname: Hlasta
mesh_terms: D000818:Animals; D008076:Cholesterol, HDL / Q000097:blood*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D008049:Lipase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013859:Thiocarbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D008076:Cholesterol, HDL; D004791:Enzyme Inhibitors; D008075:Lipoproteins, HDL; D013859:Thiocarbamates; D008049:Lipase