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.
Subject(s)
4-Quinolones/chemistry , 4-Quinolones/pharmacology , Human Umbilical Vein Endothelial Cells/drug effects , Oxidative Stress/drug effects , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , 4-Quinolones/pharmacokinetics , Animals , Cytochrome P-450 CYP2D6/metabolism , Cytochrome P-450 CYP2D6 Inhibitors , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Rats , Rats, Sprague-DawleyABSTRACT
The patient was a 58-year-old female. Though she had been in good health, increased hepatobiliary enzymes were detected in a health examination. She visited our hospital for close examination. The serum IgG4 level was normal, but ERCP and MRCP showed band-like stricture and beaded appearance of the bile ducts. A diagnosis of primary sclerosing cholangitis (PSC) was made. Since hyperlipidemia was also observed, oral administration of bezafibrate (400mg/day) alone was performed as the initial treatment, and transaminase, ALP, and GGT rapidly decreased. These results suggested that the initial administration of bezafibrate alone is effective against PSC.
