Design, Synthesis, and Evaluation of Piperazinyl Pyrrolidin-2-ones as a Novel Series of Reversible Monoacylglycerol Lipase Inhibitors

Abstract

Monoacylglycerol lipase (MAGL) is a major serine hydrolase that hydrolyzes 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA) and glycerol in the brain. Because 2-AG and AA are endogenous biologically active ligands in the brain, inhibition of MAGL is an attractive therapeutic target for CNS disorders, particularly neurodegenerative diseases. In this study, we report the structure-based drug design of novel piperazinyl pyrrolidin-2-ones starting from our hit compounds 2a and 2b. By enhancing the interaction of the piperazinyl pyrrolidin-2-one core and its substituents with the MAGL enzyme via design modifications, we identified a potent and reversible MAGL inhibitor, compound (R)-3t. Oral administration of compound (R)-3t to mice decreased AA levels and elevated 2-AG levels in the brain.

Pyrrolidin‐2‐one linked benzofused heterocycles as novel small molecule monoacylglycerol lipase inhibitors and antinociceptive agents

“…However, the 4‐methoxy phenyl part of the ligand is involved in close van der Waals interactions in the hydrophobic atmosphere of Leu148, Leu213 and Leu241. This pattern of binding is in full agreement with the inhibitor bound crystal structures reported earlier (Aida et al., 2018; Bertrand et al., 2010; Labar et al., 2010; Scalvini et al., 2016). In the formalin‐induced nociception test, compound 25 showed a dose‐dependent reduction of pain response in both acute and late phases.…”

“…Glide 5.9 implemented in Maestro 9.4 (GUI of Schrodinger) was used for extra precision (XP) docking of potential ligand (compound 25). The X‐ray crystal structure of h MAGL (PDB ID: http://5ZUN, Resolution‐1.35 Å) was retrieved from Protein Data Bank (PDB) and utilized for molecular docking study (Aida et al., 2018). Protein preparation wizard in Maestro was used for the protein structure preparation like deletion of water molecules, assignment of bond orders, the inclusion of hydrogen atoms and treatment of formal charges.…”

“…Takeda Pharmaceuticals Co. Ltd. (Kanagawa, Japan) identified a potent and reversible MAGL inhibitor (IC 50 = 3.6 n m ), comprising of piperazinyl‐linked pyrrolidin‐2‐one moiety (compound 23; Figure 1). The coordinates of the crystal structures of MAGL in complex with a piperazinyl pyrrolidin‐2‐one derivative (PDB ID: http://5ZUN) have also been reported (Aida et al., 2018). A benzoylpiperidine derivative (compound 23, IC 50 = 80 n m ) is reported as potent and selective reversible MAGL inhibitor (Granchi et al., 2019).…”

Inhibitors of lipogenic enzymes as a potential therapy against cancer

“…In 2018, a selective and reversible inhibitor of MAGL was developed by Takeda Pharmaceutical: compound 34 (Figure 5). 152 This compound with a piperazinyl pyrrolidin‐2‐one structure showed great balance between metabolic stability (29 μL/min/mg) and inhibition activity (IC 50 = 3.6 nM). The authors reported that it was selective against MAGL over FAAH, but selectivity over other serine hydrolases has not been reported yet.…”

One-Pot Three-Component Synthesis of Pyrrolidin-2-ones via a Sequential Wittig/Nucleophilic Addition/Cyclization Reaction

“…Among the many nitrogen-containing heterocycles, the pyrrolidinone scaffold is found in a large number of bioactive compounds that possess highly diverse biological properties. For examples, some pyrrolidin-2-one derivatives have been found recently to exhibit good anticancer, 1 antiviral, 2 anticonvulsant, 3 and antioxidant 4 activities, whereas others have been used as reversible monoacylglycerol lipase inhibitors, 5 -adrenoceptor antagonists, 6 and selective orexin-2 receptor antagonists. 7 As a consequence, many new synthetic methods for pyrrolidin-2-ones have been reported over the past decades.…”