Lipoprotein-associated PLA2 inhibition--a novel, non-lipid lowering strategy for atherosclerosis therapy.
Farmaco
; 56(1-2): 45-50, 2001.
Article
em En
| MEDLINE
| ID: mdl-11347966
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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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fosfolipases A
/
Arteriosclerose
/
Inibidores Enzimáticos
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Farmaco
Assunto da revista:
FARMACOLOGIA
/
QUIMICA
Ano de publicação:
2001
Tipo de documento:
Article
País de afiliação:
Reino Unido