3-Aminoazetidin-2-one derivatives as N-acylethanolamine acid amidase (NAAA) inhibitors suitable for systemic administration.
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.
Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova (Italy), Fax: (+39) 010-71781228.
Annalisa
A
Fiasella
Andrea
A
Nuzzi
Maria
M
Summa
Andrea
A
Armirotti
Glauco
G
Tarozzo
Giorgio
G
Tarzia
Marco
M
Mor
Fabio
F
Bertozzi
Tiziano
T
Bandiera
Daniele
D
Piomelli
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D051379:Mice; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship
C116379:2-azetidinone; D001384:Azetidines; D004791:Enzyme Inhibitors; D000581:Amidohydrolases; C523108:NAAA protein, human
N-acylethanolamine acid amidase; cysteine hydrolase; inhibitors; structure-activity relationships; β-lactams