title: Inhibition of secretory phospholipase A2. 1-design, synthesis and structure-activity relationship studies starting from 4-tetradecyloxybenzamidine to obtain specific inhibitors of group II sPLA2s.
abstract: Starting from 4-tetradecyloxybenzamidine (PMS815), a non-specific inhibitor of GI and GII PLA2s, we report in this work the discovery of the specificity through design, synthesis and structure-activity relationships studies of different kinds of PMS815 derivatives. The leading compound, 4,5-dihydro-3-(4-tetradecyloxybenzyl)-1,2,4-4H-oxadiazol-5-one (9b, PMS1062) exhibits a micromolar IC50 towards three group II PLA2s, while inactive towards four group I and one group III enzymes in two in vitro enzymatic assay conditions. It is also able to block the PLA2-II activities induced by LPS and IL-6 in HepG2 cell line and no cytotoxicity is observed when PMS1062 is tested up to a concentration of 100 microM in two different cell lines (A549 and LLC-PK1).
authors.affiliation: Unité de Pharmacochimie Moléculaire et Systèmes Membranaires (EA2381), Laboratoire de Pharmacochimie Moléculaire, Université Paris 7 - Denis-Diderot, case 7066, 2, place-Jussieu, 75251 Paris cedex 5, France.
authors.forename: Léon
authors.initials: L
authors.lastname: Assogba
authors.forename: Azali
authors.initials: A
authors.lastname: Ahamada-Himidi
authors.forename: Nadia Meddad-Bel
authors.initials: NM
authors.lastname: Habich
authors.forename: Darina
authors.initials: D
authors.lastname: Aoun
authors.forename: Latifa
authors.initials: L
authors.lastname: Boukli
authors.forename: France
authors.initials: F
authors.lastname: Massicot
authors.forename: Carine M
authors.initials: CM
authors.lastname: Mounier
authors.forename: Jack
authors.initials: J
authors.lastname: Huet
authors.forename: Aazdine
authors.initials: A
authors.lastname: Lamouri
authors.forename: Jean-Edouard
authors.initials: JE
authors.lastname: Ombetta
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Godfroid
authors.forename: Chang-Zhi
authors.initials: CZ
authors.lastname: Dong
authors.forename: Françoise
authors.initials: F
authors.lastname: Heymans
mesh_terms: D000818:Animals; D001550:Benzamidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001792:Blood Platelets / Q000201:enzymology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054501:Group II Phospholipases A2; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010069:Oxadiazoles / Q000737:chemistry; D010179:Pancreas / Q000201:enzymology; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D013329:Structure-Activity Relationship; D013552:Swine; D013777:Tetrazoles / Q000737:chemistry
chemical_list: C507160:4-tetradecyloxybenzamidine; D001550:Benzamidines; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D013777:Tetrazoles; D010741:Phospholipases A; D054501:Group II Phospholipases A2; C516293:PLA2G2D protein, human; D054467:Phospholipases A2