2. Academic Validation
  3. 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

  • J Med Chem. 2024 Jan 19. doi: 10.1021/acs.jmedchem.3c01278.
Stefania Butini 1,  Uwe Grether 2,  Kwang-Mook Jung 3,  Alessia Ligresti 4,  Marco Allarà 4,  Annemarieke G J Postmus 5,  Samuele Maramai 1,  Simone Brogi 6,  Alessandro Papa 1,  Gabriele Carullo 1,  David Sykes 7 8,  Dmitry Veprintsev 7,  Stefano Federico 1,  Alessandro Grillo 1,  Bruno Di Guglielmo 1,  Anna Ramunno 9,  Anna Floor Stevens 5,  Dominik Heer 2,  Stefania Lamponi 1,  Sandra Gemma 1,  Jörg Benz 2,  Vincenzo Di Marzo 4 10 11 12 13,  Mario van der Stelt 5,  Daniele Piomelli 3,  Giuseppe Campiani 1 14
Affiliations

Affiliations

  • 1 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53100 Siena, Italy.
  • 2 Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland.
  • 3 Department of Anatomy and Neurobiology, University of California Irvine, Irvine, California 92697, United States.
  • 4 Institute of Biomolecular Chemistry, National Research Council of Italy, Via Campi Flegrei 34, 80078 Pozzuoli, Italy.
  • 5 Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University and Oncode Institute, 2300 CC, Leiden, Netherlands.
  • 6 Department of Pharmacy, University of Pisa, via Bonanno, 56126 Pisa, 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 and University of Nottingham, Edgbaston, B15 2TT Birmingham, Midlands, United Kingdom.
  • 9 Department of Pharmacy/DIFARMA, University of Salerno, via Giovanni Paolo II 132, Salerno 84084, Fisciano, Italy.
  • 10 Centre Nutrition, Santé et Société (NUTRISS), Institut sur La Nutrition Et Les Aliments Fonctionnels (INAF), École de Nutrition, Université Laval, 2440 Boulevard Hochelaga, Québec G1V 0A6, Canada.
  • 11 Canada Excellence Research Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health, PO Box 2325, Quebec G1V 0A6, Canada.
  • 12 Centre de Recherche de l'Institut de Cardiologie et de Pneumologie de Québec, Faculté de Médecine, Département de Médecine, Université Laval, PO Box 2725, Québec G1V 4G5, Canada.
  • 13 Unité Mixte Internationale en Recherche Chimique et Biomoléculaire sur le Microbiome et Son Impact Sur la Santé Métabolique et la Nutrition (UMI-MicroMeNu), Université Laval, PO Box 2325, Quebec G1V 0A6, Canada.
  • 14 Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan 81746-7346, Iran.
PMID: 38241614 DOI: 10.1021/acs.jmedchem.3c01278
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.

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