RESUMO
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).
Assuntos
Benzamidinas/química , Benzamidinas/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/química , Fosfolipases A/antagonistas & inibidores , Animais , Benzamidinas/síntese química , Plaquetas/enzimologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Fosfolipases A2 do Grupo II , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Oxidiazóis/química , Pâncreas/enzimologia , Fosfolipases A2 , Relação Estrutura-Atividade , Suínos , Tetrazóis/químicaRESUMO
We have recently reported the discovery of a series of specific inhibitors of human group IIA phospholipase A(2) (hGIIA PLA(2)) to display promising in vitro and in vivo properties. Here we describe the influence of different structural modifications on the specificity and potency against hGIIA PLA(2) versus porcine group IB PLA(2). The SAR results, as well as the logP and pK(a) values of oxadiazolone determined in this work, provide important information towards the comprehension of the mode of action of this kind of compounds.