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

Stefania ButiniUwe GretherKwang-Mook JungAlessia LigrestiMarco AllaràAnnemarieke G J PostmusSamuele MaramaiSimone BrogiAlessandro PapaGabriele CarulloDavid SykesDmitry B VeprintsevStefano FedericoAlessandro GrilloBruno Di GuglielmoAnna RamunnoAnna Floor StevensDominik HeerStefania LamponiSandra GemmaJörg BenzVincenzo Di MarzoMario van der SteltDaniele PiomelliGiuseppe Campiani
Published in: Journal of medicinal chemistry (2024)
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 (3 R ,4 S )- 5v is one of the most potent irreversible inhibitors of h / m MAGL identified thus far. These results suggest that the new MAGL inhibitors have therapeutic potential for different central and peripheral pathologies.
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