title: Synthesis and structure-activity relationship (SAR) of 2-methyl-4-oxo-3-oxetanylcarbamic acid esters, a class of potent N-acylethanolamine acid amidase (NAAA) inhibitors.
abstract: N-Acylethanolamine acid amidase (NAAA) is a lysosomal cysteine hydrolase involved in the degradation of saturated and monounsaturated fatty acid ethanolamides (FAEs), a family of endogenous lipid agonists of peroxisome proliferator-activated receptor-α, which include oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). The β-lactone derivatives (S)-N-(2-oxo-3-oxetanyl)-3-phenylpropionamide (2) and (S)-N-(2-oxo-3-oxetanyl)-biphenyl-4-carboxamide (3) inhibit NAAA, prevent FAE hydrolysis in activated inflammatory cells, and reduce tissue reactions to pro-inflammatory stimuli. Recently, our group disclosed ARN077 (4), a potent NAAA inhibitor that is active in vivo by topical administration in rodent models of hyperalgesia and allodynia. In the present study, we investigated the structure-activity relationship (SAR) of threonine-derived β-lactone analogues of compound 4. The main results of this work were an enhancement of the inhibitory potency of β-lactone carbamate derivatives for NAAA and the identification of (4-phenylphenyl)-methyl-N-[(2S,3R)-2-methyl-4-oxo-oxetan-3-yl]carbamate (14q) as the first single-digit nanomolar inhibitor of intracellular NAAA activity (IC50 = 7 nM on both rat NAAA and human NAAA).
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia , Via Morego 30, I-16163 Genova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ponzano
authors.forename: Fabio
authors.initials: F
authors.lastname: Bertozzi
authors.forename: Luisa
authors.initials: L
authors.lastname: Mengatto
authors.forename: Mauro
authors.initials: M
authors.lastname: Dionisi
authors.forename: Andrea
authors.initials: A
authors.lastname: Armirotti
authors.forename: Elisa
authors.initials: E
authors.lastname: Romeo
authors.forename: Anna
authors.initials: A
authors.lastname: Berteotti
authors.forename: Claudio
authors.initials: C
authors.lastname: Fiorelli
authors.forename: Glauco
authors.initials: G
authors.lastname: Tarozzo
authors.forename: Angelo
authors.initials: A
authors.lastname: Reggiani
authors.forename: Andrea
authors.initials: A
authors.lastname: Duranti
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
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
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D001483:Base Sequence; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship; D053719:Tandem Mass Spectrometry
chemical_list: D002219:Carbamates; D017931:DNA Primers; D004791:Enzyme Inhibitors; D000581:Amidohydrolases; C523108:NAAA protein, human