Discovery of 1,5-Diphenylpyrazole-3-Carboxamide Derivatives as Potent, Reversible, and Selective Monoacylglycerol Lipase (MAGL) Inhibitors

Monoacylglycerol lipase (MAGL) is
a serine hydrolase that plays
an important role in the degradation of the endocannabinoid neurotransmitter
2-arachidonoylglycerol, which is implicated in many physiological
processes. Beyond the possible utilization of MAGL inhibitors as anti-inflammatory,
antinociceptive, and anticancer agents, their application has encountered
obstacles due to the unwanted effects caused by the irreversible inhibition
of this enzyme. The possible application of reversible MAGL inhibitors
has only recently been explored, mainly due to the deficiency of known
compounds possessing efficient reversible inhibitory activities. In
this work, we report a new series of reversible MAGL inhibitors. Among
them, compound 26 showed to be a potent MAGL inhibitor
(IC50 = 0.51 μM, Ki =
412 nM) with a good selectivity versus fatty acid amide hydrolase
(FAAH), α/β-hydrolase domain-containing 6 (ABHD6), and
12 (ABHD12). Interestingly, this compound also possesses antiproliferative
activities against two different cancer cell lines and relieves the
neuropathic hypersensitivity induced in vivo by oxaliplatin.