Design, synthesis, and biological evaluation of oxazolidone derivatives as highly potent N-acylethanolamine acid amidase (NAAA) inhibitors
Design, synthesis, and biological evaluation of oxazolidone derivatives as highly potent N-acylethanolamine acid amidase (NAAA) inhibitors
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作为高效 N-酰基乙醇胺酰胺酶 (NAAA) 抑制剂的恶唑烷酮衍生物的设计、合成和生物学评价
DOI：
10.1039/c6ra28734d
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发表时间：
2017-01-01
期刊：
影响因子：
3.9
通讯作者：
Qiu, Yan
中科院分区：
文献类型：
--
作者：
Ren, Jie;Li, Yuhang;Qiu, Yan
N-乙醇胺水解酸酰胺酶(NAAA)是一种能催化N-棕榈酰乙醇酰胺(PEA)等内源脂肪酸乙醇酰胺(FAE)水解的溶酶体酶。豌豆通过结合过氧化物酶体增殖物激活受体α(PPAR-α)具有抗炎和镇痛活性。通过抑制NAAA来阻止PEA的降解已被认为是治疗炎症和疼痛的一种新策略。在本研究中，我们发现了恶唑酮衍生物作为一种新型的NAAA抑制剂支架，并通过修饰侧链和末端亲脂取代基来研究其构效关系(SAR)。结果表明，C5链长、直链和饱和链长是抑制NAAA的首选构型。介绍了几种纳米NAAA抑制剂，包括2f、3h、3i和3j，其IC50值分别为270 nM、150 nM、100 nM和190 nM。酶降解研究表明，2f以选择性、非竞争性和可逆的方式抑制NAAA。此外，2f具有较高的抗炎和镇痛活性。
N-Acylethanolamine-hydrolyzing acid amidase (NAAA) is a lysosomal enzyme that catalyzes the hydrolysis of endogenous fatty acid ethanolamides (FAEs), such as N-palmitoylethanolamide (PEA). PEA exhibits anti-inflammatory and analgesic activities by engaging peroxisome proliferator-activated receptor α (PPAR-α). Preventing PEA degradation by inhibition of NAAA has been proposed as a novel strategy for the treatment of inflammation and pain. In the present study, we reported the discovery of the oxazolidone derivative as a novel scaffold for NAAA inhibitors, and studied the structure–activity relationship (SAR) by modification of the side chain and terminal lipophilic substituents. The results showed that the link chain length of C5, straight and saturated linkages were the preferred shape patterns for NAAA inhibition. Several nanomolar NAAA inhibitors were described, including 2f, 3h, 3i and 3j with IC50 values of 270 nM, 150 nM, 100 nM and 190 nM, respectively. Enzymatic degradation studies suggested that 2f inhibited NAAA in a selective, noncompetitive and reversible pattern. Moreover, 2f showed high anti-inflammatory and analgesic activities after systemic and oral administration.