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 |
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Authors: | Afshin Ghasemi Alwine Schulze Elfringhoff Matthias Lehr |
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Institution: | Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Hittorfstrasse 58-62, D-48149, Münster, Germany |
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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. |
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Keywords: | Cytosolic phospholipase A2 inhibitors 3-dodecanoylindole-2-carboxylic acid structure–activity relationships inhibition |
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