title: Synthesis, structure-activity, and structure-stability relationships of 2-substituted-N-(4-oxo-3-oxetanyl) N-acylethanolamine acid amidase (NAAA) inhibitors.
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.
authors.affiliation: Drug Discovery & Development, Italian Institute of Technology (IIT), Via Morego 30, 16163 Genova (Italy).
authors.forename: Romina
authors.initials: R
authors.lastname: Vitale
authors.forename: Giuliana
authors.initials: G
authors.lastname: Ottonello
authors.forename: Rita
authors.initials: R
authors.lastname: Petracca
authors.forename: Sine Mandrup
authors.initials: SM
authors.lastname: Bertozzi
authors.forename: Stefano
authors.initials: S
authors.lastname: Ponzano
authors.forename: Andrea
authors.initials: A
authors.lastname: Armirotti
authors.forename: Anna
authors.initials: A
authors.lastname: Berteotti
authors.forename: Mauro
authors.initials: M
authors.lastname: Dionisi
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
authors.forename: Tiziano
authors.initials: T
authors.lastname: Bandiera
authors.forename: Fabio
authors.initials: F
authors.lastname: Bertozzi
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007783:Lactones; D000581:Amidohydrolases; C523108:NAAA protein, human
keywords: N-acylethanolamine acid amidase; inhibitors; stability; structure-activity relationships; β-lactones