Lipoprotein-associated PLA2 inhibition--a novel, non-lipid lowering strategy for atherosclerosis therapy.

Abstract

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.

• Authors: C A Leach, D M Hickey, R J Ife, C H Macphee, S A Smith, D G Tew
• Journal: Farmaco (Societa chimica italiana : 1989) (Farmaco) 2001 Jan-Feb Vol. 56 Issue 1-2 Pg. 45-50 ISSN: 0014-827X [Print] France
• PMID: 11347966 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Phospholipases A
• Phospholipases A2
• 1-Alkyl-2-acetylglycerophosphocholine Esterase

Topics

• 1-Alkyl-2-acetylglycerophosphocholine Esterase
• Arteriosclerosis (drug therapy, etiology)
• Enzyme Inhibitors (therapeutic use)
• Humans
• Phospholipases A (antagonists & inhibitors)
• Phospholipases A2
• Structure-Activity Relationship