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

• Published in: Journal of medicinal chemistry Vol. 56; no. 17; pp. 6917 - 6934
• Main Authors: Ponzano, Stefano, Bertozzi, Fabio, Mengatto, Luisa, Dionisi, Mauro, Armirotti, Andrea, Romeo, Elisa, Berteotti, Anna, Fiorelli, Claudio, Tarozzo, Glauco, Reggiani, Angelo, Duranti, Andrea, Tarzia, Giorgio, Mor, Marco, Cavalli, Andrea, Piomelli, Daniele, Bandiera, Tiziano
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.09.2013; Amer Chemical Soc
• Subjects: Amidohydrolases - antagonists & inhibitors; Base Sequence; Carbamates - chemical synthesis; Carbamates - chemistry; Carbamates - pharmacology; Chemistry, Medicinal; DNA Primers; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Models, Molecular; Pharmacology & Pharmacy; Science & Technology; Spectroscopy, Fourier Transform Infrared; Structure-Activity Relationship; Tandem Mass Spectrometry; ALCOHOLS; PALMITOYLETHANOLAMIDE; AMINES; INFLAMMATION; EDEMA; PROTEOLYTIC ACTIVATION; DI(2-PYRIDYL) CARBONATE; HYDROLASE; REVEALS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm400739u

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).