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

The serine hydrolases cytosolic phospholipase Aα (cPLAα) 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 cPLAα and FAAH reflecting differences in the binding mode to the enzymes. Furthermore, the metabolic stability of the target structures was investigated .