Development of Potent and Selective Monoacylglycerol Lipase Inhibitors. SARs, Structural Analysis, and Biological Characterization

New
potent, selective monoacylglycerol lipase (MAGL) inhibitors
based on the azetidin-2-one scaffold ((±)-5a–v, (±)-6a–j, and (±)-7a–d) were developed as irreversible ligands,
as demonstrated by enzymatic and crystallographic studies for (±)-5d, (±)-5l, and (±)-5r. X-ray analyses combined with extensive computational studies allowed
us to clarify the binding mode of the compounds. 5v was
identified as selective for MAGL when compared with other serine hydrolases.
Solubility, in vitro metabolic stability, cytotoxicity,
and absence of mutagenicity were determined for selected analogues.
The most promising compounds ((±)-5c, (±)-5d, and (±)-5v) were used for in
vivo studies in mice, showing a decrease in MAGL activity
and increased 2-arachidonoyl-sn-glycerol levels in
forebrain tissue. In particular, 5v is characterized
by a high eudysmic ratio and (3R,4S)-5v is one of the most potent irreversible inhibitors
of h/mMAGL identified thus far.
These results suggest that the new MAGL inhibitors have therapeutic
potential for different central and peripheral pathologies.