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3‐Aminoazetidin‐2‐one Derivatives as N ‐Acylethanolamine Acid Amidase (NAAA) Inhibitors Suitable for Systemic Administration
Author(s) -
Fiasella Annalisa,
Nuzzi Andrea,
Summa Maria,
Armirotti Andrea,
Tarozzo Glauco,
Tarzia Giorgio,
Mor Marco,
Bertozzi Fabio,
Bandiera Tiziano,
Piomelli Daniele
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300546
Subject(s) - palmitoylethanolamide , amidase , chemistry , pharmacology , fatty acid amide hydrolase , hydrolysis , biochemistry , receptor , antagonist , biology , cannabinoid receptor
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.