European journal of medicinal chemistry

Structure-activity relationship studies on 1-(2-oxopropyl)indole-5-carboxylic acids acting as inhibitors ofxa0cytosolic phospholipase A2α: Effect of substituents at the indole 3-position on activity, solubility, and metabolic stability.

PMID 27810597


Cytosolic phospholipase A2α (cPLA2α) is a key enzyme in the biosynthesis of pro-inflammatory lipid mediators and therefore represents an attractive target for the development of new anti-inflammatory drugs. Recently, we have found that 1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid (4) is a potent inhibitor of the enzyme. In this work, we evaluate the effect of butanoyl- and hexanoyl-substituents in position 3 of the indole scaffold of this compound bearing terminal groups of varying polarity. As a result, inhibitory potency was not affected considerably in most cases, while metabolic phase I and phase II inxa0vitro stability and aqueous solubility could be influenced and modulated by the structural modifications performed.