Synthesis, biological evaluation, and structure-activity relationships of 3-acylindole-2-carboxylic acids as inhibitors of the cytosolic phospholipase A2.

3-Acylindole-2-carboxylic acid derivatives were prepared and evaluated for their ability to inhibit the cytosolic phospholipase A2 of intact bovine platelets. To define the structural requirements for enzyme inhibition, the carboxylic acid group, the acyl residue, and the moiety in position 1 were systematically modified. Furthermore, different substituents were introduced into the phenyl part of the indole. Replacement of the carboxylic acid group in position 2 of the indole with an acetic or propionic acid substituent led to a decrease of inhibitory potency. Enzyme inhibition was optimal when the acyl residue in position 3 had a length of 12 or more carbons. Conformational restriction of the acyl residue did not influence activity. Introduction of alkyl chains at position 1 of the indole with 8 or more carbons resulted in a loss of activity. However, replacing the omega-methyl group of such compounds with a carboxylic acid moiety was found to increase inhibitory potency significantly. Among the tested indole derivatives, 1-[2-(4-carboxyphenoxy)ethyl]-3-dodecanoylindole-2-carboxyli c acid (29b) had the highest potency. With an IC50 of 0.5 microM it was about 20-fold more active than the standard cPLA2 inhibitor arachidonyl trifluoromethyl ketone (IC50: 11 microM).