Synthesis, activity and metabolic stability of propan-2-one substituted tetrazolylalkanoic acids as dual inhibitors of cytosolic phospholipase A2α and fatty acid amide hydrolase

The serine hydrolases cytosolic Phospholipase A₂α (cPLA₂α) and fatty acid amide hydrolase (FAAH) are interesting targets for the development of new anti-inflammatory and analgesic drugs. Structural modifications of a potent dual inhibitor with a propan-2-one substituted tetrazolylpropionic acid moiety led to compounds with also nanomolar activity against both enzymes but better physicochemical properties. The structure-activity relationships showed that the variations had partially divergent effects on the inhibitory activity of the compounds towards cPLA₂α and FAAH reflecting differences in the binding mode to the enzymes. Furthermore, the metabolic stability of the target structures was investigated in vitro.