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

Article abstract of DOI:10.1021/jm960863w

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 Ω-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-carboxylic acid (29b) had the highest potency. With an IC₅₀ of 0.5 μM it was about 20-fold more active than the standard cPLA₂ inhibitor arachidonyl trifiuoromethyl ketane (IC₅₀: 11μM).