Inhibition of Secreted Phospholipase A2. 4-Glycerol Derivatives of 4,5-Dihydro-3-(4-tetradecyloxybenzyl)-1,2,4-4H-oxadiazol-5-one with Broad Activities

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• 作者：Mohamed Touaibia ; Atimé ; Djimdé ; Fei Cao ; Eric Boilard ; Sofiane Bezzine ; Gé ; rard Lambeau ; Catherine Redeuilh ; Aazdine Lamouri ; France Massicot ; Franç ; ois Chau ; Chang-Zhi Dong
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：April 5, 2007
• 年：2007
• 卷：50
• 期：7
• 页码：1618 - 1626
• 全文大小：136K
• 年卷期：v.50,no.7(April 5, 2007)
• ISSN：1520-4804

文摘

Secreted phospholipases A₂ (sPLA₂s) have been reported to play an important role in various inflammatoryconditions and thus represent an attractive therapeutic target. Previous SAR studies from our laboratoryhave revealed certain important features of our recently discovered specific hGIIA sPLA₂ inhibitors, andwe report here the synthesis and biological activities of glycerol-containing derivatives of our lead compoundIII (Figure 1). Efficient and selective synthesis methods have been developed to make glycerol trisubstitutedby different groups on desired positions. In terms of biological activities, the best compounds (A3, A6, andA15) are more active than III (Figure 1), as potent as Me-Indoxam, an sPLA₂s inhibitor of reference, againsthGIIA, hGV, and hGX sPLA₂s and at least 10 times less active toward the GIB enzymes in two in vitroassay systems. By synthesis of enantiopure (S)-A6, we demonstrated that no important improvement of theinhibitory potency could be achieved by this approach. Furthermore, the results show that the globallipophilicity is likely responsible for the anti-PLA₂ activity and two oxadiazolone moieties seem too big tobe accommodated by the active site of the hGIIA enzyme.