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.

A new series of carbamoyl tetrazoles has been synthesized and evaluated as inhibitors of FAAH and MAGL and as TRPV1 and TRPA1 modulators.Figure optionsDownload 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.