title: Identification of 4-quinolone derivatives as inhibitors of reactive oxygen species production from human umbilical vein endothelial cells.
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.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. kenichi.onda@jp.astellas.com
authors.forename: Kenichi
authors.initials: K
authors.lastname: Onda
authors.forename: Fumie
authors.initials: F
authors.lastname: Narazaki
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishibashi
authors.forename: Keita
authors.initials: K
authors.lastname: Nakanishi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sawada
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Imamura
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Momose
authors.forename: Shigetada
authors.initials: S
authors.lastname: Furukawa
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Shimada
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Moriguchi
authors.forename: Masamichi
authors.initials: M
authors.lastname: Yuda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kayakiri
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohta
mesh_terms: D042462:4-Quinolones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D042462:4-Quinolones; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D017382:Reactive Oxygen Species; D019389:Cytochrome P-450 CYP2D6