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Optimization of a Benzoylpiperidine Class Identifies a Highly Potent and Selective Reversible Monoacylglycerol Lipase (MAGL) Inhibitor.
Journal article

Optimization of a Benzoylpiperidine Class Identifies a Highly Potent and Selective Reversible Monoacylglycerol Lipase (MAGL) Inhibitor.

  • Granchi C Department of Pharmacy , University of Pisa , Via Bonanno 6 , 56126 Pisa , Italy.
  • Lapillo M Department of Pharmacy , University of Pisa , Via Bonanno 6 , 56126 Pisa , Italy.
  • Glasmacher S Institute of Biochemistry and Molecular Medicine, NCCR TransCure , University of Bern , CH-3012 Bern , Switzerland.
  • Bononi G Department of Pharmacy , University of Pisa , Via Bonanno 6 , 56126 Pisa , Italy.
  • Licari C Department of Pharmacy , University of Pisa , Via Bonanno 6 , 56126 Pisa , Italy.
  • Poli G Department of Pharmacy , University of Pisa , Via Bonanno 6 , 56126 Pisa , Italy.
  • El Boustani M Pathology Unit, Department of Molecular Biology and Translational Research , National Cancer Institute and Center for Molecular Biomedicine , 33081 Aviano , Pordenone , Italy.
  • Caligiuri I Pathology Unit, Department of Molecular Biology and Translational Research , National Cancer Institute and Center for Molecular Biomedicine , 33081 Aviano , Pordenone , Italy.
  • Rizzolio F Pathology Unit, Department of Molecular Biology and Translational Research , National Cancer Institute and Center for Molecular Biomedicine , 33081 Aviano , Pordenone , Italy.
  • Gertsch J Institute of Biochemistry and Molecular Medicine, NCCR TransCure , University of Bern , CH-3012 Bern , Switzerland.
  • Macchia M Department of Pharmacy , University of Pisa , Via Bonanno 6 , 56126 Pisa , Italy.
  • Minutolo F Department of Pharmacy , University of Pisa , Via Bonanno 6 , 56126 Pisa , Italy.
  • Tuccinardi T Department of Pharmacy , University of Pisa , Via Bonanno 6 , 56126 Pisa , Italy.
  • Chicca A Institute of Biochemistry and Molecular Medicine, NCCR TransCure , University of Bern , CH-3012 Bern , Switzerland.
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  • 2019-02-05
Published in:
  • Journal of medicinal chemistry. - 2019
Animals
Antineoplastic Agents
Brain
Catalytic Domain
Cell Line, Tumor
Cell Proliferation
Drug Design
Enzyme Inhibitors
Humans
Male
Mice, Inbred C57BL
Molecular Docking Simulation
Molecular Dynamics Simulation
Molecular Structure
Monoacylglycerol Lipases
Piperidines
Protein Binding
Structure-Activity Relationship
English Monoacylglycerol lipase (MAGL) is the enzyme degrading the endocannabinoid 2-arachidonoylglycerol, and it is involved in several physiological and pathological processes. The therapeutic potential of MAGL is linked to several diseases, including cancer. The development of MAGL inhibitors has been greatly limited by the side effects associated with the prolonged MAGL inactivation. Importantly, it could be preferable to use reversible MAGL inhibitors in vivo, but nowadays only few reversible compounds have been developed. In the present study, structural optimization of a previously developed class of MAGL inhibitors led to the identification of compound 23, which proved to be a very potent reversible MAGL inhibitor (IC50 = 80 nM), selective for MAGL over the other main components of the endocannabinoid system, endowed of a promising antiproliferative activity in a series of cancer cell lines and able to block MAGL both in cell-based as well as in vivo assays.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://susi.usi.ch/global/documents/206378
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