Lipoprotein-associated PLA2 inhibition--a novel, non-lipid lowering strategy for atherosclerosis therapy.
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a serine lipase that is associated with low density lipoprotein (LDL) in human plasma. Substrates include oxidised phosphatidylcholine (PC), which is hydrolysed by Lp-PLA2 to lyso-PC and oxidised fatty acids. Both products are bioactive and proinflammatory, and implicated in monocyte infiltration into the developing plaque, deposition of foam cells, and plaque progression and instability. Lp-PLA2 has recently been shown to be a risk factor for coronary events in previously asymptomatic, hypercholesterolaemic men. A series of azetidinones was designed as potent and selective inhibitors of this enzyme; SB-222657 inhibited release of the chemotactic cleavage products from oxidised LDL, and SB-244323 reduced atherosclerotic plaque development in a 3 month rabbit study. A series of pyrimidones has been designed from a screening hit, and nanomolar inhibitors identified. Oral efficacy in inhibiting plasma Lp-PLA2 in rabbits has been demonstrated with a variety of structural classes.
Leach
C A
CA
Glaxo SmithKline, New Frontiers Science Park, Harlow, Essex, UK. colin_leach-1@sbphrd.com
Hickey
D M
DM
Ife
R J
RJ
Macphee
C H
CH
Smith
S A
SA
Tew
D G
DG
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000209:etiology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D010741:Phospholipases A; D054467:Phospholipases A2; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase