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

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

  • J Med Chem. 2016 Nov 23;59(22):10299-10314. doi: 10.1021/acs.jmedchem.6b01459.
Carlotta Granchi 1,  Flavio Rizzolio 2,  Stefano Palazzolo 2 3,  Sara Carmignani 1,  Marco Macchia 1,  Giuseppe Saccomanni 1,  Clementina Manera 1,  Adriano Martinelli 1,  Filippo Minutolo 1,  Tiziano Tuccinardi 1
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Pisa , Via Bonanno 6, 56126 Pisa, Italy.
  • 2 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.
  • 3 Graduate School in Nanotechnology, University of Trieste , 34127 Trieste, Italy.
PMID: 27809504 DOI: 10.1021/acs.jmedchem.6b01459
Abstract

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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