Butini_2024_J.Med.Chem__

Reference

Title : Development of Potent and Selective Monoacylglycerol Lipase Inhibitors. SARs, Structural Analysis, and Biological Characterization - Butini_2024_J.Med.Chem__
Author(s) : Butini S , Grether U , Jung KM , Ligresti A , Allara M , Postmus AGJ , Maramai S , Brogi S , Papa A , Carullo G , Sykes D , Veprintsev D , Federico S , Grillo A , Di Guglielmo B , Ramunno A , Stevens AF , Heer D , Lamponi S , Gemma S , Benz J , Di Marzo V , van der Stelt M , Piomelli D , Campiani G
Ref : Journal of Medicinal Chemistry , : , 2024
Abstract :

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.

PubMedSearch : Butini_2024_J.Med.Chem__
PubMedID: 38241614
Gene_locus related to this paper: human-MGLL

Citations formats

Butini S, Grether U, Jung KM, Ligresti A, Allara M, Postmus AGJ, Maramai S, Brogi S, Papa A, Carullo G, Sykes D, Veprintsev D, Federico S, Grillo A, Di Guglielmo B, Ramunno A, Stevens AF, Heer D, Lamponi S, Gemma S, Benz J, Di Marzo V, van der Stelt M, Piomelli D, Campiani G (2024)
Development of Potent and Selective Monoacylglycerol Lipase Inhibitors. SARs, Structural Analysis, and Biological Characterization
Journal of Medicinal Chemistry :

Butini S, Grether U, Jung KM, Ligresti A, Allara M, Postmus AGJ, Maramai S, Brogi S, Papa A, Carullo G, Sykes D, Veprintsev D, Federico S, Grillo A, Di Guglielmo B, Ramunno A, Stevens AF, Heer D, Lamponi S, Gemma S, Benz J, Di Marzo V, van der Stelt M, Piomelli D, Campiani G (2024)
Journal of Medicinal Chemistry :