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

Development of Potent and Selective Monoacylglycerol Lipase Inhibitors. Sars, Structural Analysis, and Biological Characterization Publisher Pubmed

Butini S¹ ; Grether U² ; Jung KM³ ; Ligresti A⁴ ; Allara M⁴ ; Postmus AGJ⁵ ; Maramai S¹ ; Brogi S⁶ ; Papa A¹ ; Carullo G¹ ; Sykes D^{7, 8} ; Veprintsev D⁷ ; Federico S¹ ; Grillo A¹ Show All Authors

Butini S¹
Grether U²
Jung KM³
Ligresti A⁴
Allara M⁴
Postmus AGJ⁵
Maramai S¹
Brogi S⁶
Papa A¹
Carullo G¹
Sykes D^{7, 8}
Veprintsev D⁷
Federico S¹
Grillo A¹
Di Guglielmo B¹
Ramunno A⁹
Stevens AF⁵
Heer D²
Lamponi S¹
Gemma S¹
Benz J²
Di Marzo V^{4, 10, 11, 12, 13}
Van Der Stelt M⁵
Piomelli D³
Campiani G^{1, 14}

Show Affiliations

1. Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, Siena, 53100, Italy
2. Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, CH-4070, Switzerland
3. Department of Anatomy and Neurobiology, University of California Irvine, Irvine, 92697, CA, United States
4. Institute of Biomolecular Chemistry, National Research Council of Italy, Via Campi Flegrei 34, Pozzuoli, 80078, Italy
5. Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University and Oncode Institute, Leiden, 2300 CC, Netherlands
6. Department of Pharmacy, University of Pisa, via Bonanno, Pisa, 56126, Italy
7. Faculty of Medicine & Health Sciences, University of Nottingham, Nottingham, NG7 2UH, United Kingdom
8. Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, University of Nottingham, Edgbaston, Midlands, Birmingham, B15 2TT, United Kingdom
9. Department of Pharmacy/DIFARMA, University of Salerno, via Giovanni Paolo II 132, Fisciano, Salerno, 84084, Italy
10. Centre Nutrition, Sante et Societe (NUTRISS), Institut sur La Nutrition Et Les Aliments Fonctionnels (INAF), Ecole de Nutrition, Universite Laval, 2440 Boulevard Hochelaga, Quebec, G1V 0A6, Canada
11. Canada Excellence Research Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health, Quebec, G1V 0A6, Canada
12. Centre de Recherche de l’Institut de Cardiologie et de Pneumologie de Quebec, Faculte de Medecine, Departement de Medecine, Universite Laval, PO Box 2725, Quebec, G1V 4G5, Canada
13. Unite Mixte Internationale en Recherche Chimique et Biomoleculaire sur le Microbiome et Son Impact Sur la Sante Metabolique et la Nutrition (UMI-MicroMeNu), Universite Laval, Quebec, G1V 0A6, Canada
14. Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, 81746-7346, Iran

Source: Journal of Medicinal Chemistry Published: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. © 2024 American Chemical Society.

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Style	Citing Format
MLA	Butini S, et al.. "Development of Potent and Selective Monoacylglycerol Lipase Inhibitors. Sars, Structural Analysis, and Biological Characterization." Journal of Medicinal Chemistry, vol. 67, no. 3, 2024, pp. 1758-1782.
APA	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, ... Campiani G (2024). Development of Potent and Selective Monoacylglycerol Lipase Inhibitors. Sars, Structural Analysis, and Biological Characterization. Journal of Medicinal Chemistry, 67(3), 1758-1782.
Chicago	Butini S, Grether U, Jung KM, Ligresti A, Allara M, Postmus AGJ, Maramai S, et al.. "Development of Potent and Selective Monoacylglycerol Lipase Inhibitors. Sars, Structural Analysis, and Biological Characterization." Journal of Medicinal Chemistry 67, no. 3 (2024): 1758-1782.
Harvard	Butini S et al. (2024) 'Development of Potent and Selective Monoacylglycerol Lipase Inhibitors. Sars, Structural Analysis, and Biological Characterization', Journal of Medicinal Chemistry, 67(3), pp. 1758-1782.
Vancouver	Butini S, Grether U, Jung KM, Ligresti A, Allara M, Postmus AGJ, et al.. Development of Potent and Selective Monoacylglycerol Lipase Inhibitors. Sars, Structural Analysis, and Biological Characterization. Journal of Medicinal Chemistry. 2024;67(3):1758-1782.
BibTex	@article{ author = {Butini S and Grether U and Jung KM and Ligresti A and Allara M and Postmus AGJ and Maramai S and Brogi S and Papa A and Carullo G and Sykes D and Veprintsev D and Federico S and Grillo A and Di Guglielmo B and Ramunno A and Stevens AF and Heer D and Lamponi S and Gemma S and Benz J and Di Marzo V and Van Der Stelt M and Piomelli D and Campiani G}, title = {Development of Potent and Selective Monoacylglycerol Lipase Inhibitors. Sars, Structural Analysis, and Biological Characterization}, journal = {Journal of Medicinal Chemistry}, volume = {67}, number = {3}, pages = {1758-1782}, year = {2024} }
RIS	TY - JOUR AU - Butini S AU - Grether U AU - Jung KM AU - Ligresti A AU - Allara M AU - Postmus AGJ AU - Maramai S AU - Brogi S AU - Papa A AU - Carullo G AU - Sykes D AU - Veprintsev D AU - Federico S AU - Grillo A AU - Di Guglielmo B AU - Ramunno A AU - Stevens AF AU - Heer D AU - Lamponi S AU - Gemma S AU - Benz J AU - Di Marzo V AU - Van Der Stelt M AU - Piomelli D AU - Campiani G TI - Development of Potent and Selective Monoacylglycerol Lipase Inhibitors. Sars, Structural Analysis, and Biological Characterization JO - Journal of Medicinal Chemistry VL - 67 IS - 3 SP - 1758 EP - 1782 PY - 2024 ER -

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