Cytosolic phospholipase A2 (cPLA2) and secreted phospholipase A2 (sPLA2) play a major role in the production of arachidonic acid and various eicosanoids, for example PGE2, in cells. We have recently reported that a long chain oxoamide based on α-(S)-leucine (GK126) presents interesting inhibition of sPLA2.1 In addition a simple amide derivative of γ-(R)-norleucine (GK115) showed inhibition of sPLA2.2 The purpose of the present work was to study the effect of these two sPLA2 inhibitors on the suppression of PGE2 formation in mesangial cells and to identify novel small peptides that will be able to cause such an effect. Cultures of renal mesangial cells were stimulated for 24 h with interleukin 1 plus forskolin to trigger a huge increase of PGE2 synthesis. Cells were treated in the absence or presence of increasing concentrations of sPLA2 inhibitors. Supernatants were collected and taken for a PGE2-ELISA to quantify PGE2 released from the cells. Both sPLA2 inhibitors GK126 and GK115 presented interesting suppression of PGE2 formation. After these promising results, we continued our project carrying out molecular docking studies to understand if small peptide derivatives based on either α-leucine or γ-norleucine may interact with sPLA2. Some of the peptide derivatives that presented interesting binding score were synthesized and tested for their effect on rat mesangial cells. We were pleased to find that benzoyl-glycyl-glycyl-γ-(R)-norleucine showed an interesting effect on the suppression of PGE2 formation. Thus, we have identified a lead for the development of novel agents that can be used to treat inflammatory diseases.