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

Journal of medicinal chemistry 2024 Feb 08

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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 (3R,4S)-5v is one of the most potent irreversible inhibitors of h/mMAGL identified thus far. These results suggest that the new MAGL inhibitors have therapeutic potential for different central and peripheral pathologies.

Citation

Stefania Butini, Uwe Grether, Kwang-Mook Jung, Alessia Ligresti, Marco Allarà, Annemarieke G J Postmus, Samuele Maramai, Simone Brogi, Alessandro Papa, Gabriele Carullo, David Sykes, Dmitry Veprintsev, Stefano Federico, Alessandro Grillo, Bruno Di Guglielmo, Anna Ramunno, Anna Floor Stevens, Dominik Heer, Stefania Lamponi, Sandra Gemma, Jörg Benz, Vincenzo Di Marzo, Mario van der Stelt, Daniele Piomelli, Giuseppe Campiani. Development of Potent and Selective Monoacylglycerol Lipase Inhibitors. SARs, Structural Analysis, and Biological Characterization. Journal of medicinal chemistry. 2024 Feb 08;67(3):1758-1782