Structural Optimization of 4‑Chlorobenzoylpiperidine Derivatives for the Development of Potent, Reversible, and Selective Monoacylglycerol Lipase (MAGL) Inhibitors

Monoacylglycerol lipase (MAGL) inhibitors
are considered potential
therapeutic agents for a variety of pathological conditions, including
several types of cancer. Many MAGL inhibitors are reported in literature;
however, most of them showed an irreversible mechanism of action,
which caused important side effects. The use of reversible MAGL inhibitors
has been only partially investigated so far, mainly because of the
lack of compounds with good MAGL reversible inhibition properties.
In this study, starting from the (4-(4-chlorobenzoyl)­piperidin-1-yl)­(4-methoxyphenyl)­methanone
(CL6a) lead compound that showed a reversible mechanism of MAGL inhibition
(Ki = 8.6 μM), we started its structural
optimization and we developed a new potent and selective MAGL inhibitor
(17b, Ki = 0.65 μM).
Furthermore, modeling studies suggested that the binding interactions
of this compound replace a structural water molecule reproducing its
H-bonds in the MAGL binding site, thus identifying a new key anchoring
point for the development of new MAGL inhibitors.