Structure–activity relationship studies of 3-dodecanoylindole-2-carboxylic acid inhibitors of cytosolic phospholipase A₂α-mediated arachidonic acid release in intact platelets: variation of the keto moiety

Abstract

Recently we found that 1-methyldodecanoylindole-2-carboxylic acid (1) and 1-[2-(4-carboxyphenoxy)ethyl]-3-dodecanoylindole-2-carboxylic acid (4) were inhibitors of the cytosolic phospholipase A₂α (cPLA₂α)-mediated arachidonic acid release in calcium ionophore A23187-stimulated human platelets with IC₅₀-values of 4.8 μM (1) and 0.86 μM (4). We have now replaced the 3-acyl residue of these compounds by alkylated sulfinyl-, sulfony-, sulfinamoyl-, sulfamoyl-, carbonylamino-, or carbonylaminomethyl-substituents. Structure–activity relationship studies revealed that the pronounced cellular activity of 4 strongly depends on the presence of the 3-acyl moiety. Surprisingly, when testing 4 and its derivatives in an assay with the isolated cPLA₂, none of these compounds showed an inhibitory potency at 10 μM indicating that they do not inhibit cPLA₂α in the cells by a direct interaction with the active site of the enzyme.

Keywords::

• Cytosolic phospholipase A₂
• inhibitors
• 3-dodecanoylindole-2-carboxylic acid
• structure–activity relationships
• inhibition