Biaryl tetrazolyl ureas as inhibitors of endocannabinoid metabolism: Modulation at the N-portion and distal phenyl ring

In the present study, we have further extended the structure–activity relationships for the tetrazolyl ureas class of compounds as potential FAAH and/or MAGL inhibitors, by replacing the dimethylamino group of the parent compounds 1 and 2 with bulkier groups or by introducing on the distal phenyl ring of 1 and 2 a selected set of substituents. Some of the new compounds (16, 20, 21, 25, and 28) inhibited FAAH potently (IC50 = 3.0–9.7 nM) and selectively (39- to more than 141-fold) over MAGL, while tetrazole 27 turned out to be a promising dual FAAH–MAGL inhibitor of potential therapeutic use. Covalent docking studies on FAAH indicated that the binding modes of tetrazoles 1–32 did not display a unique pattern. The ability of tetrazoles 1–32 to act as TRPV1 and TRPA1 modulators was also investigated.

Graphical abstractA new series of carbamoyl tetrazoles has been synthesized and evaluated as inhibitors of FAAH and MAGL and as TRPV1 and TRPA1 modulators.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► A series of 30 new biaryl tetrazolyl ureas has been synthesized. ► Some of the prepared compounds inhibited FAAH potently and selectively over MAGL. ► The action on TRPV1 and TRPA1 channels was also investigated. ► Results were discussed using covalent docking.