5962-86-7Relevant academic research and scientific papers
3-Aminoazetidin-2-one derivatives as N-acylethanolamine acid amidase (NAAA) inhibitors suitable for systemic administration
Fiasella, Annalisa,Nuzzi, Andrea,Summa, Maria,Armirotti, Andrea,Tarozzo, Glauco,Tarzia, Giorgio,Mor, Marco,Bertozzi, Fabio,Bandiera, Tiziano,Piomelli, Daniele
, p. 1602 - 1614 (2014/07/21)
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.
