Discovery of XEN445: a potent and selective endothelial lipase inhibitor raises plasma HDL-cholesterol concentration in mice

Bioorg Med Chem. 2013 Dec 15;21(24):7724-34. doi: 10.1016/j.bmc.2013.10.023. Epub 2013 Oct 28.

Abstract

Endothelial lipase (EL) activity has been implicated in HDL metabolism and in atherosclerotic plaque development; inhibitors are proposed to be efficacious in the treatment of dyslipidemia related cardiovascular disease. We describe here the discovery of a novel class of anthranilic acids EL inhibitors. XEN445 (compound 13) was identified as a potent and selective EL inhibitor, that showed good ADME and PK properties, and demonstrated in vivo efficacy in raising plasma HDLc concentrations in mice.

Keywords: Anthranilic acid; Cardiovascular disease; Endothelial lipase inhibitors; HDL cholesterol.

MeSH terms

  • Animals
  • Benzoates / chemical synthesis
  • Benzoates / chemistry
  • Benzoates / pharmacology*
  • Cholesterol, HDL / blood*
  • Cholesterol, HDL / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Lipase / antagonists & inhibitors*
  • Lipase / deficiency
  • Lipase / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Structure
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology*
  • Structure-Activity Relationship

Substances

  • 2-(3-(pyridin-2-ylmethoxy)pyrrolidin-1-yl)-5-(trifluoromethyl)benzoic acid
  • Benzoates
  • Cholesterol, HDL
  • Enzyme Inhibitors
  • Pyrrolidines
  • Lipase