Design and Synthesis of Potent N-Acylethanolamine-hydrolyzing Acid Amidase (NAAA) Inhibitor as Anti-Inflammatory Compounds
Date
2012-08-20Author
Li, Yuhang
Yang, Longhe
Chen, Ling
Zhu, Chenggang
Huang, Rui
Zheng, Xiao
Qiu, Yan
邱彦
Fu, Jin
Collections
- 公共卫生-已发表论文 [571]
Abstract
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.
Citation
PLOS ONE,2012,7(8)URI
http://dx.doi.org/10.1371/journal.pone.0043023WOS:000307733800042
https://dspace.xmu.edu.cn/handle/2288/14911