Synthesis and Structure鈥揂ctivity Relationship (SAR) of 2-Methyl-4-oxo-3-oxetanylcarbamic Acid Esters, a Class of Potent N-Acylethanolamine Acid Amidase (NAAA) Inhibitors

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• 作者：Stefano Ponzano ; Fabio Bertozzi ; Luisa Mengatto ; Mauro Dionisi ; Andrea Armirotti ; Elisa Romeo ; Anna Berteotti ; Claudio Fiorelli ; Glauco Tarozzo ; Angelo Reggiani ; Andrea Duranti ; Giorgio Tarzia ; Marco Mor ; Andrea Cavalli ; Daniele Piomelli ; Tiziano Bandiera
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：September 12, 2013
• 年：2013
• 卷：56
• 期：17
• 页码：6917-6934
• 全文大小：676K
• 年卷期：v.56,no.17(September 12, 2013)
• ISSN：1520-4804

文摘

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-伪, which include oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). The 尾-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鈥揳ctivity relationship (SAR) of threonine-derived 尾-lactone analogues of compound 4. The main results of this work were an enhancement of the inhibitory potency of 尾-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).