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

被引：38

作者：

Leach, CA ^{[1
]}

Hickey, DMB ^{[1
]}

Ife, RJ ^{[1
]}

Macphee, CH ^{[1
]}

Smith, SA ^{[1
]}

Tew, DG ^{[1
]}

机构：

[1] Glaxo SmithKline, Harlow CM19 5AW, Essex, England

来源：

FARMACO | 2001年 / 56卷 / 1-2期

关键词：

phospholipase A(2); Lp-PLA(2); atherosclerosis therapy; enzyme inhibitors;

D O I：

10.1016/S0014-827X(01)01011-4

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) 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-PLA(2) 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-PLA(2) 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-PLA(2) in rabbits has been demonstrated with a variety of structural classes. (C) 2001 Elsevier Science S.A. All rights reserved.

引用

页码：45 / 50

页数：6

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