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	Design and Synthesis of Potent N-Acylethanolamine-hydrolyzing Acid Amidase (NAAA) Inhibitor as Anti-Inflammatory Compounds
	Li, Yuhang ; Yang, Longhe ; Chen, Ling ; Zhu, Chenggang ; Huang, Rui ; Zheng, Xiao ; Qiu, Yan ; Qiu Y(邱彦) ; Fu, Jin
	2012-08-20
关键词	MOLECULAR CHARACTERIZATION HYDROLASE PALMITOYLETHANOLAMIDE ANANDAMIDE INFLAMMATION CERAMIDASE ACTIVATION STABILITY MECHANISM DISCOVERY
英文摘要	N-acylethanolamine-hydrolyzing acid amidase (NAAA) is a lysosomal enzyme involved in biological deactivation of N-palmitoylethanolamide (PEA), which exerts anti-inflammatory and analgesic effects through the activation of nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR-alpha). To develop selective and potent NAAA inhibitors, we designed and synthesized a series of derivatives of 1-pentadecanyl-carbonyl pyrrolidine (compound 1), a general amidase inhibitor. Structure activity relationship (SAR) studies have identified a compound 16, 1-(2-Biphenyl-4-yl) ethyl-carbonyl pyrrolidine, which has shown the highest inhibition on NAAA activity (IC50 = 2.12 +/- 0.41 mu M) and is characterized as a reversible and competitive NAAA inhibitor. Computational docking analysis and mutagenesis study revealed that compound 16 interacted with Asparagine 209 (Asn(209)) residue flanking the catalytic pocket of NAAA so as to block the substrate entrance. In vitro pharmacological studies demonstrated that compound 16 dose-dependently reduced mRNA expression levels of iNOS and IL-6, along with an increase of intracellular PEA levels, in mouse macrophages with lipopolysaccharides (LPS) induced inflammation. Our study discovered a novel NAAA inhibitor, compound 16, that could serve as a potential anti-inflammatory agent.; Xiamen Science and Technology Key Program, China [3502Z20100006]; Fundamental Research Fund for China Universities [2011121056]; National Natural Science Foundation of China [91129722]
语种	英语
出版者	PUBLIC LIBRARY SCIENCE
内容类型	期刊论文
源URL	[http://dx.doi.org/10.1371/journal.pone.0043023]
专题	公共卫生－已发表论文
推荐引用方式 GB/T 7714	Li, Yuhang,Yang, Longhe,Chen, Ling,et al. Design and Synthesis of Potent N-Acylethanolamine-hydrolyzing Acid Amidase (NAAA) Inhibitor as Anti-Inflammatory Compounds[J],2012.
APA	Li, Yuhang.,Yang, Longhe.,Chen, Ling.,Zhu, Chenggang.,Huang, Rui.,...&Fu, Jin.(2012).Design and Synthesis of Potent N-Acylethanolamine-hydrolyzing Acid Amidase (NAAA) Inhibitor as Anti-Inflammatory Compounds..
MLA	Li, Yuhang,et al."Design and Synthesis of Potent N-Acylethanolamine-hydrolyzing Acid Amidase (NAAA) Inhibitor as Anti-Inflammatory Compounds".(2012).

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