Inhibitors of cytosolic phospholipase A2α with carbamate structure: synthesis, biological activity, metabolic stability, and bioavailability

Cytosolic phospholipase A2α is a serine hydrolase involved in the generation of pro-inflammatory lipid mediators. Here, we describe structure–activity relationship studies on a series of carbamate-substituted indazole-5-carboxylic acid inhibitors of this enzyme. Bioavailability experiments in mice with 1-(3-(4-butylphenoxy)-2-{[(ethylthio)carbonyl]amino}propyl)indazole-5-carboxylic acid (14) revealed a high rate of glucuronidation and biliary excretion of this compound. Replacement of the rigid aromatic carboxylic acid system by a more flexible aliphatic one led to substances with a significantly increased in vitro stability against metabolic glucuronidation.