title: 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.
abstract: Secreted phospholipases A2 (sPLA2s) have been reported to play an important role in various inflammatory conditions and thus represent an attractive therapeutic target. Previous SAR studies from our laboratory have revealed certain important features of our recently discovered specific hGIIA sPLA2 inhibitors, and we report here the synthesis and biological activities of glycerol-containing derivatives of our lead compound III (Figure 1). Efficient and selective synthesis methods have been developed to make glycerol trisubstituted by different groups on desired positions. In terms of biological activities, the best compounds (A3, A6, and A15) are more active than III (Figure 1), as potent as Me-Indoxam, an sPLA2s inhibitor of reference, against hGIIA, hGV, and hGX sPLA2s and at least 10 times less active toward the GIB enzymes in two in vitro assay systems. By synthesis of enantiopure (S)-A6, we demonstrated that no important improvement of the inhibitory potency could be achieved by this approach. Furthermore, the results show that the global lipophilicity is likely responsible for the anti-PLA2 activity and two oxadiazolone moieties seem too big to be accommodated by the active site of the hGIIA enzyme.
authors.affiliation: Unité de Pharmacochimie Moléculaire et Systèmes Membranaires (EA2381), Université Paris7-Denis Diderot, case 7066, 2 place Jussieu, 75251 Paris, Cedex 05, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Touaibia
authors.forename: Atimé
authors.initials: A
authors.lastname: Djimdé
authors.forename: Fei
authors.initials: F
authors.lastname: Cao
authors.forename: Eric
authors.initials: E
authors.lastname: Boilard
authors.forename: Sofiane
authors.initials: S
authors.lastname: Bezzine
authors.forename: Gérard
authors.initials: G
authors.lastname: Lambeau
authors.forename: Catherine
authors.initials: C
authors.lastname: Redeuilh
authors.forename: Aazdine
authors.initials: A
authors.lastname: Lamouri
authors.forename: France
authors.initials: F
authors.lastname: Massicot
authors.forename: François
authors.initials: F
authors.lastname: Chau
authors.forename: Chang-Zhi
authors.initials: CZ
authors.lastname: Dong
authors.forename: Françoise
authors.initials: F
authors.lastname: Heymans
mesh_terms: D005990:Glycerol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D054501:Group II Phospholipases A2; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000737:chemistry; D054467:Phospholipases A2; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D010069:Oxadiazoles; D010741:Phospholipases A; D054501:Group II Phospholipases A2; C516293:PLA2G2D protein, human; D054467:Phospholipases A2; D005990:Glycerol