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Structural Optimization of 4-Chlorobenzoylpiperidine Derivatives for the Development of Potent, Reversible, and Selective Monoacylglycerol Lipase (MAGL) Inhibitors

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Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
Division of Experimental and Clinical Pharmacology, Department of Molecular Biology and Translational Research, National Cancer Institute and Center for Molecular Biomedicine, IRCCS, 33081 Aviano, Pordenone, Italy
§ Graduate School in Nanotechnology, University of Trieste, 34127 Trieste, Italy
*Phone: +39 050 2219595. Fax: +39 050 2210680. E-mail: [email protected]
Cite this: J. Med. Chem. 2016, 59, 22, 10299–10314
Publication Date (Web):November 3, 2016
https://doi.org/10.1021/acs.jmedchem.6b01459
Copyright © 2016 American Chemical Society

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    Abstract

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    Monoacylglycerol lipase (MAGL) inhibitors are considered potential therapeutic agents for a variety of pathological conditions, including several types of cancer. Many MAGL inhibitors are reported in literature; however, most of them showed an irreversible mechanism of action, which caused important side effects. The use of reversible MAGL inhibitors has been only partially investigated so far, mainly because of the lack of compounds with good MAGL reversible inhibition properties. In this study, starting from the (4-(4-chlorobenzoyl)piperidin-1-yl)(4-methoxyphenyl)methanone (CL6a) lead compound that showed a reversible mechanism of MAGL inhibition (Ki = 8.6 μM), we started its structural optimization and we developed a new potent and selective MAGL inhibitor (17b, Ki = 0.65 μM). Furthermore, modeling studies suggested that the binding interactions of this compound replace a structural water molecule reproducing its H-bonds in the MAGL binding site, thus identifying a new key anchoring point for the development of new MAGL inhibitors.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.6b01459.

    • Clustering analysis, docking results of compound 17c and 17a, MD simulation analysis of 17b, 1H NMR spectra of compound 12c, interference analysis for compound 17b, effect of DTT on the 17b inhibition properties, cell growth inhibitory activities of compounds 17b, 2, and 3, IC50 plot of MAGL inhibition of compound 43, analytical data on intermediate compounds, HPLC chromatograms and NMR spectra of the final compounds (PDF)

    • Molecular formula strings (CSV)

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