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3-Aminoazetidin-2-one Derivatives as N-Acylethanolamine Acid Amidase (NAAA) Inhibitors Suitable for Systemic Administration

Authors

  • Dr. Annalisa Fiasella,

    1. Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova (Italy), Fax: (+39) 010-71781228
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    • These authors contributed equally to this work.

  • Dr. Andrea Nuzzi,

    1. Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova (Italy), Fax: (+39) 010-71781228
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    • These authors contributed equally to this work.

  • Dr. Maria Summa,

    1. Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova (Italy), Fax: (+39) 010-71781228
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  • Dr. Andrea Armirotti,

    1. Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova (Italy), Fax: (+39) 010-71781228
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  • Dr. Glauco Tarozzo,

    1. Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova (Italy), Fax: (+39) 010-71781228
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  • Prof. Giorgio Tarzia,

    1. Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino “Carlo Bo”, Piazza del Rinascimento 6, 61029 Urbino (Italy)
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  • Prof. Marco Mor,

    1. Dipartimento di Farmacia, Università degli Studi di Parma, Viale della Scienze 27A, 43124 Parma (Italy)
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  • Dr. Fabio Bertozzi,

    1. Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova (Italy), Fax: (+39) 010-71781228
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  • Dr. Tiziano Bandiera,

    Corresponding author
    1. Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova (Italy), Fax: (+39) 010-71781228
    • Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova (Italy), Fax: (+39) 010-71781228===

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  • Prof. Daniele Piomelli

    Corresponding author
    1. Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova (Italy), Fax: (+39) 010-71781228
    2. Departments of Anatomy & Neurobiology, Pharmacology, and Biological Chemistry, University of California, Irvine, 3216 Gillespie Neuroscience Facility, Irvine, CA 92697-4621 (USA)
    • Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova (Italy), Fax: (+39) 010-71781228===

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Abstract

N-Acylethanolamine acid amidase (NAAA) is a cysteine hydrolase that catalyzes the hydrolysis of endogenous lipid mediators such as palmitoylethanolamide (PEA). PEA has been shown to exert anti-inflammatory and antinociceptive effects in animals by engaging peroxisome proliferator-activated receptor α (PPAR-α). Thus, preventing PEA degradation by inhibiting NAAA may provide a novel approach for the treatment of pain and inflammatory states. Recently, 3-aminooxetan-2-one compounds were identified as a class of highly potent NAAA inhibitors. The utility of these compounds is limited, however, by their low chemical and plasma stabilities. In the present study, we synthesized and tested a series of N-(2-oxoazetidin-3-yl)amides as a novel class of NAAA inhibitors with good potency and improved physicochemical properties, suitable for systemic administration. Moreover, we elucidated the main structural features of 3-aminoazetidin-2-one derivatives that are critical for NAAA inhibition.

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