Design of new potent and selective secretory phospholipase A2 inhibitors. 6-Synthesis, structure–activity relationships and molecular modelling of 1-substituted-4-[4,5-dihydro-1,2,4-(4H)-oxadiazol-5-one-3-yl(methyl)]-functionalized aryl piperazin/one/dione derivatives

Abstract: The group IIA human non-pancreatic secretory phospholipase A2 (hnp-sPLA2) is one of the enzymes implied in the inflammatory process. In the course of our work on inhibitors of this enzyme we investigated the influence of rigidity of the piperazine region on the biological activity. Several modifications were explored. Various linkers, such as amide, urea, carbamate, or alkoxyphenyl were inserted between the piperazine and the lipophilic chain. Also, modification of the piperazine core to incorporate carbonyl groups was studied. In an in vitro fluorimetric assay using the human GIIA (HPLA2) and porcine pancreatic GIB enzymes, compound 60a (Y=phenoxy, R=C18H37, Z=CH2) had the optimal activity with an IC50 =30nM on HPLA2. By means of molecular modelling we attempted to get informations towards comprehension of differences in activity. [Copyright &y& Elsevier]