Synthesis, activity, metabolic stability and cell permeability of new cytosolic phospholipase A(2)alpha inhibitors with 1-indolyl-3-phenoxypropan-2-one structure

Cytosolic phospholipase A(2)alpha (cPLA(2)alpha), the key enzyme of the arachidonic acid cascade, is considered to be an interesting target for the development of new anti-inflammatory drugs. Potent inhibitors of the enzyme include indole-5-carboxylic acids with propan-2-one residues in position 1 of the indole. Previously, it was found that central pharmacophoric elements of these compounds are their ketone and carboxylic acid groups, which unfortunately are subject to pronounced metabolism by carbonyl reductases and glucuronosyltransferases, respectively. Here we show that the metabolic stability of these inhibitors can be improved by introducing alkyl substituents in the vicinity of the ketone group or by increasing their rigidity. Furthermore, permeability tests with Caco-2 cells revealed that the indole derivatives have only low permeability, which can be attributed to their affinity to efflux transporters. Among other things, the polar ketone group in the center of the molecules seems to be a decisive factor for their reverse transport. After its removal, the permeability increased significantly. The enhancement in metabolic stability and permeability achieved by the structural variations carried out was accompanied by a more or less pronounced decrease in the inhibitory potency of the compounds against cPLA(2)alpha.

Automated summary

Cytosolic phospholipase A(2)alpha (cPLA(2)alpha) is an interesting target for new anti-inflammatory drug development. The metabolic stability and permeability of potent inhibitors can be improved by introducing alkyl substituents or increasing rigidity near the ketone group. The polar ketone group is a decisive factor in the reverse transport of molecules, and its removal significantly increases permeability. However, these structural variations may lead to a decrease in the inhibitory potency against cPLA(2)alpha.