Potent inhibitors of lipoprotein-associated phospholipase A(2): benzaldehyde O-heterocycle-4-carbonyloxime.
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.
Jeong
Hyung Jae
HJ
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.
Park
Yong-Dae
YD
Park
Ho-Yong
HY
Jeong
Il Yun
IY
Jeong
Tae-Sook
TS
Lee
Woo Song
WS
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001547:Benzaldehydes / Q000494:pharmacology*; D006801:Humans; D010091:Oximes / Q000494:pharmacology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors*
D001547:Benzaldehydes; D010091:Oximes; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase