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Synthesis, Structure–Activity, and Structure–Stability Relationships of 2‐Substituted‐ N ‐(4‐oxo‐3‐oxetanyl) N ‐Acylethanolamine Acid Amidase (NAAA) Inhibitors
Author(s) -
Vitale Romina,
Ottonello Giuliana,
Petracca Rita,
Bertozzi Sine Mandrup,
Ponzano Stefano,
Armirotti Andrea,
Berteotti Anna,
Dionisi Mauro,
Cavalli Andrea,
Piomelli Daniele,
Bandiera Tiziano,
Bertozzi Fabio
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.201300416
Subject(s) - amidase , palmitoylethanolamide , chemistry , stereochemistry , amide , amino acid , structure–activity relationship , biochemistry , receptor , hydrolysis , agonist , in vitro , cannabinoid receptor
Abstract N ‐Acylethanolamine acid amidase (NAAA) is a cysteine amidase that preferentially hydrolyzes saturated or monounsaturated fatty acid ethanolamides (FAEs), such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), which are endogenous agonists of nuclear peroxisome proliferator‐activated receptor‐α (PPAR‐α). Compounds that feature an α‐amino‐β‐lactone ring have been identified as potent and selective NAAA inhibitors and have been shown to exert marked anti‐inflammatory effects that are mediated through FAE‐dependent activation of PPAR‐α. We synthesized and tested a series of racemic, diastereomerically pure β‐substituted α‐amino‐β‐lactones, as either carbamate or amide derivatives, investigating the structure–activity and structure–stability relationships (SAR and SSR) following changes in β‐substituent size, relative stereochemistry at the α‐ and β‐positions, and α‐amino functionality. Substituted carbamate derivatives emerged as more active and stable than amide analogues, with the cis configuration being generally preferred for stability. Increased steric bulk at the β‐position negatively affected NAAA inhibitory potency, while improving both chemical and plasma stability.