Structure-activity relationships in platelet activating factor .9. From PAF-antagonism to PLA(2) inhibition

被引：7

作者：

Binisti, C ^{[1
]}

Touboul, E ^{[1
]}

Mounier, C ^{[1
]}

Heymans, F ^{[1
]}

Bon, C ^{[1
]}

Godfroid, JJ ^{[1
]}

机构：

[1] INST PASTEUR, UNITE VENINS, F-75724 PARIS 15, FRANCE

来源：

JOURNAL OF LIPID MEDIATORS AND CELL SIGNALLING | 1997年 / 15卷 / 02期

关键词：

piperazine; inflammation; phospholipase A(2) inhibitor; structure-activity relationship;

D O I：

10.1016/S0929-7855(96)00453-1

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Many important mediators of inflammation result from the liberation of free arachidonic acid from phospholipid pools, which arise from the action of phospholipase A(2) (PLA(2)). Therefore the inhibition of this enzyme would be an important treatment in many inflammatory disease slates. Starting from a series of compounds which are known as PAF-antagonists, we have synthesized new molecules. These new compounds inhibited various secretory PLA(2)s, with IC50's in the mu mol range. This allowed us to analyze the structure-activity relationships for PLA(2) inhibition. The results showed that inhibition of secretory PLA(2) depends on the length of the alkyl chain, with an optimum for 13 to 17 carbons, which is in agreement with X-ray crystallographic and nuclear magnetic resonance (NMR) studies on the active site of PLA(2)s, and that a free nitrogen on the piperazine ring is required to ensure a good inhibitory potency.

引用

页码：125 / 144

页数：20

共 44 条

[1] DISCOVERY OF NEW NON-PHOSPHOLIPID INHIBITORS OF THE SECRETORY PHOSPHOLIPASES A(2) [J].