Design and synthesis of potent N-acylethanolamine-hydrolyzing acid amidase (NAAA) inhibitor as anti-inflammatory compounds.
Design and synthesis of potent N-acylethanolamine-hydrolyzing acid amidase (NAAA) inhibitor as anti-inflammatory compounds.
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设计和合成有效的 N-酰基乙醇胺水解酸酰胺酶 (NAAA) 抑制剂作为抗炎化合物。
DOI：
10.1371/journal.pone.0043023
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Fu J
中科院分区：
文献类型：
--
作者：
Li Y;Yang L;Chen L;Zhu C;Huang R;Zheng X;Qiu Y;Fu J
N-酰基乙醇胺水解酸性酰胺酶（NAAA）是一种参与N-棕榈酰乙醇胺（PEA）生物失活的溶酶体酶，PEA通过激活核受体过氧化物酶体增殖物激活受体α（PPAR-α）发挥抗炎镇痛作用。为了开发选择性强的NAAA抑制剂，我们设计并合成了一系列酰胺酶抑制剂1-十五烷基羰基吡咯烷（化合物1）的衍生物。构效关系（SAR）研究已经鉴定了化合物16，1-（2-联苯-4-基）乙基-羰基吡咯烷，其对NAAA活性显示出最高的抑制作用（IC 50 = 2.12±0.41 µM），并被表征为可逆和竞争性NAAA抑制剂。 计算对接分析和诱变研究表明，化合物16与NAAA催化口袋侧翼的天冬酰胺209（Asn 209）残基相互作用，从而阻断底物进入。体外药理学研究表明，在脂多糖（LPS）诱导的炎症的小鼠巨噬细胞中，化合物16剂量依赖性地降低iNOS和IL-6的mRNA表达水平，同时沿着细胞内PEA水平的增加。我们的研究发现了一种新的NAAA抑制剂，化合物16，可以作为一种潜在的抗炎剂。
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-α). 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 µM) and is characterized as a reversible and competitive NAAA inhibitor. Computational docking analysis and mutagenesis study revealed that compound 16 interacted with Asparagine 209 (Asn209) 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.