Hexafluoroisopropyl Carbamates as Selective MAGL and Dual MAGL/FAAH Inhibitors: Biochemical and Physicochemical Properties

A series of hexafluoroisopropyl carbamates with indolylalkyl‐ and azaindolylalkyl‐substituents at the carbamate nitrogen was synthesized and evaluated for inhibition of the endocannabinoid degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The synthesized derivatives with butyl to heptyl spacers between the heteroaryl and the carbamate moiety were inhibitors of both enzymes. For investigated compounds in which the alkyl chain was partially incorporated into a piperidine ring, different results were obtained. Compounds with a methylene spacer between the piperidine ring and the heteroaromatic system were found to be selective MAGL inhibitors, while an extension of the alkyl spacer to two to four atoms resulted in dual inhibition of FAAH/MAGL. The only small change in enzyme inhibitory activity with variation of the heteroaromatic system indicates that the reactive hexafluoroisopropyl carbamate group is mainly responsible for the strength of the inhibitory effect of the compounds. Selected derivatives were also tested for hydrolytic stability in aqueous solution, liver homogenate and blood plasma as well as for aqueous solubility and for permeability in a Caco‐2 cell model. Some compounds showed a slightly higher MAGL inhibitory effect than the known selective MAGL inhibitor ABX‐1431 and also partly surpassed this substance with regard to certain physicochemical and biochemical properties such as water solubility and cell permeability.