title: Potent inhibitors of lipoprotein-associated phospholipase A(2): benzaldehyde O-heterocycle-4-carbonyloxime.
abstract: A series of multi-substituted oximes were prepared and their potencies for inhibiting lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity were evaluated in vitro. Among them, compounds 3a, 3b, and 3m were identified to display a micromolar potency for inhibiting Lp-PLA(2) in whole human plasma and isolated human LDL. Based on these results, structure-activity relationship was studied on modification of three parts of R(1), R(2), and R(3) to identify a potent pharmacophore for Lp-PLA(2). In an attempt to introduce various functional groups at R(2) and R(3), we discovered that replacement of less lipophilic groups led to an increase of inhibitory activity. Among the tested oxime derivatives, cyano- and morpholino-substituted analogue 4f at R(2) and R(3) had the highest potency with an IC(50) value of 0.05 microM in whole human plasma.
authors.affiliation: National Research Laboratory of Lipid Metabolism and Atherosclerosis, Insect Resources Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-805, Republic of Korea.
authors.forename: Hyung Jae
authors.initials: HJ
authors.lastname: Jeong
authors.forename: Yong-Dae
authors.initials: YD
authors.lastname: Park
authors.forename: Ho-Yong
authors.initials: HY
authors.lastname: Park
authors.forename: Il Yun
authors.initials: IY
authors.lastname: Jeong
authors.forename: Tae-Sook
authors.initials: TS
authors.lastname: Jeong
authors.forename: Woo Song
authors.initials: WS
authors.lastname: Lee
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001547:Benzaldehydes / Q000494:pharmacology*; D006801:Humans; D010091:Oximes / Q000494:pharmacology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors*
chemical_list: D001547:Benzaldehydes; D010091:Oximes; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase