Download MendeleyDevelopment of Potent and Selective Monoacylglycerol Lipase Inhibitors. SARs, Structural Analysis, and Biological Characterization.
Butini, S., Grether, U., Jung, K.M., Ligresti, A., Allara, M., Postmus, A.G.J., Maramai, S., Brogi, S., Papa, A., Carullo, G., Sykes, D., Veprintsev, D., Federico, S., Grillo, A., Di Guglielmo, B., Ramunno, A., Stevens, A.F., Heer, D., Lamponi, S., Gemma, S., Benz, J., Di Marzo, V., van der Stelt, M., Piomelli, D., Campiani, G.(2024) J Med Chem 67: 1758-1782
- PubMed: 38241614
- DOI: https://doi.org/10.1021/acs.jmedchem.3c01278
- Primary Citation of Related Structures:
8PTC, 8PTQ, 8PTR - PubMed Abstract:
New potent, selective monoacylglycerol lipase (MAGL) inhibitors based on the azetidin-2-one scaffold ((¡À)- 5a - v , (¡À)- 6a - j , and (¡À)- 7a - d ) were developed as irreversible ligands, as demonstrated by enzymatic and crystallographic studies for (¡À)- 5d , (¡À)- 5l , and (¡À)- 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 ((¡À)- 5c , (¡À)- 5d , and (¡À)- 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.
Organizational Affiliation:
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53100 Siena, Italy.
