Azetidine and Piperidine Carbamates as Efficient, Covalent Inhibitors of Monoacylglycerol Lipase

Monoacylglycerol
lipase (MAGL) is the main enzyme responsible for
degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) in
the CNS. MAGL catalyzes the conversion of 2-AG to arachidonic acid
(AA), a precursor to the proinflammatory eicosannoids such as prostaglandins.
Herein we describe highly efficient MAGL inhibitors, identified through
a parallel medicinal chemistry approach that highlighted the improved
efficiency of azetidine and piperidine-derived carbamates. The discovery
and optimization of 3-substituted azetidine carbamate irreversible
inhibitors of MAGL were aided by the generation of inhibitor-bound
MAGL crystal structures. Compound 6, a highly efficient
and selective MAGL inhibitor against recombinant enzyme and in a cellular
context, was tested in vivo and shown
to elevate central 2-AG levels at a 10 mg/kg dose.