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