Identification of 4-quinolone derivatives as inhibitors of reactive oxygen species production from human umbilical vein endothelial cells

Bioorg Med Chem Lett. 2011 Nov 15;21(22):6861-6. doi: 10.1016/j.bmcl.2011.09.015. Epub 2011 Sep 10.

Abstract

Oxidative stress is widely recognized as being associated with a number of disorders, including metabolic dysfunction and atherosclerosis. A series of substituted 4-quinolone derivatives were prepared and evaluated as inhibitors of reactive oxygen species (ROS) production from human umbilical vein endothelial cells (HUVECs). One compound in particular, 2-({[4-(3-hydroxy-3-methylbutoxy)pyridin-2-yl]oxy}methyl)-3-methylquinolin-4(1H)-one (25b), inhibited ROS production from HUVECs with an IC(50) of 140 nM. This compound also exhibited low CYP2D6 inhibitory activity, high aqueous solubility, and good in vitro metabolic stability. An in vivo pharmacokinetic study of this compound in SD rats revealed high oral bioavailability and a long plasma half-life.

MeSH terms

  • 4-Quinolones / chemistry*
  • 4-Quinolones / pharmacokinetics
  • 4-Quinolones / pharmacology*
  • Animals
  • Cytochrome P-450 CYP2D6 / metabolism
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Human Umbilical Vein Endothelial Cells / drug effects*
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Oxidative Stress / drug effects*
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / antagonists & inhibitors*
  • Reactive Oxygen Species / metabolism*

Substances

  • 4-Quinolones
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Reactive Oxygen Species
  • Cytochrome P-450 CYP2D6