RESUMEN

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).

Asunto(s)

Benzamidinas/química , Benzamidinas/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/química , Fosfolipasas A/antagonistas & inhibidores , Animales , Benzamidinas/síntesis química , Plaquetas/enzimología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Fosfolipasas A2 Grupo II , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Oxadiazoles/química , Páncreas/enzimología , Fosfolipasas A2 , Relación Estructura-Actividad , Porcinos , Tetrazoles/química