Identification of highly potent N-acylethanolamine acid amidase (NAAA) inhibitors: Optimization of the terminal phenyl moiety of oxazolidone derivatives
Identification of highly potent N-acylethanolamine acid amidase (NAAA) inhibitors: Optimization of the terminal phenyl moiety of oxazolidone derivatives
复制标题
高效 N-酰基乙醇胺酰胺酶 (NAAA) 抑制剂的鉴定：恶唑烷酮衍生物末端苯基部分的优化
DOI：
10.1016/j.ejmech.2017.08.004
复制
发表时间：
2017-10-20
影响因子：
6.7
通讯作者：
Lu, Canzhong
中科院分区：
文献类型：
--
作者：
Li, Yuhang;Chen, Qi;Lu, Canzhong
N-acylethanolamine acid amidase (NAAA) is a cysteine hydrolase that participates in the deactivation of fatty acid ethanolamides, such as palmitoylethanolamide (PEA). NAAA inhibition may provide a potential therapeutic strategy for the treatment of diseases in which higher PEA level is desired. In the present study, we reported the structure-activity relationship (SAR) studies for oxazolidone derivatives as NAAA inhibitors. A series of substituents or alkyl replacements for the terminal phenyl ring of oxazolidone derivatives were examined. The results showed that the inhibition potency of these oxazolidone derivatives towards NAAA depends on the sizes, flexibility, and lipophilicity of the terminal groups. SAR results suggested that small lipophilic 3-phenyl substituents or hydroxy-containing 4-phenyl substituents were preferable for optimal potency. Furthermore, the distal aliphatic replacement is also preferred for high inhibitory potency. Rapid dilution and kinetic analysis suggested that oxazolidone derivatives with different terminal phenyl moieties inhibited NAAA via different mechanisms. This study identified several highly potent NAAA inhibitors, including 1a (F215, IC50 = 0.009 mu M), 10 (IC50 = 0.061 mu M) and 2e (IC50 = 0.092 mu M), and also determined structural requirements of oxazolidone derivatives for potent inhibition against NAAA. (C) 2017 Published by Elsevier Masson SAS.
