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. Stability is the key: α-Amino-β-lactams were synthesized as amide derivatives, and the effect of the azetidin-2-one ring, the stereochemistry at the α-position, and the functionalization of the α-amino group were studied with regard to N-acylethanolamine acid amidase inhibitory potency and hydrolytic and plasma stability.

3-Aminoazetidin-2-one Derivatives asN-Acylethanolamine Acid Amidase (NAAA) Inhibitors Suitable for Systemic Administration / Annalisa, Fiasella; Andrea, Nuzzi; Maria, Summa; Andrea, Armirotti; Glauco, Tarozzo; Giorgio, Tarzia; Mor, Marco; Fabio, Bertozzi; Tiziano, Bandiera; Daniele, Piomelli. - In: CHEMMEDCHEM. - ISSN 1860-7179. - 9:(2014), pp. 1602-1614. [10.1002/cmdc.201300546]

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

MOR, Marco;
2014

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. Stability is the key: α-Amino-β-lactams were synthesized as amide derivatives, and the effect of the azetidin-2-one ring, the stereochemistry at the α-position, and the functionalization of the α-amino group were studied with regard to N-acylethanolamine acid amidase inhibitory potency and hydrolytic and plasma stability.
3-Aminoazetidin-2-one Derivatives asN-Acylethanolamine Acid Amidase (NAAA) Inhibitors Suitable for Systemic Administration / Annalisa, Fiasella; Andrea, Nuzzi; Maria, Summa; Andrea, Armirotti; Glauco, Tarozzo; Giorgio, Tarzia; Mor, Marco; Fabio, Bertozzi; Tiziano, Bandiera; Daniele, Piomelli. - In: CHEMMEDCHEM. - ISSN 1860-7179. - 9:(2014), pp. 1602-1614. [10.1002/cmdc.201300546]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2761506
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