Synthesis, biological evaluation, and structure activity relationship (SAR) study of pyrrolidine amide derivatives as N-acylethanolamine acid amidase (NAAA) inhibitors
Synthesis, biological evaluation, and structure activity relationship (SAR) study of pyrrolidine amide derivatives as N-acylethanolamine acid amidase (NAAA) inhibitors
复制标题
N-酰基乙醇胺酰胺酶（NAAA）抑制剂吡咯烷酰胺衍生物的合成、生物学评价和结构活性关系（SAR）研究
作者：
Zhou Pan;Xiang Lei;Zhao Dongsheng;Ren Jie;Qiu Yan;Li Yuhang
N-酰基乙醇胺酸酰胺酶（NAAA）是脂肪酸乙醇酰胺（FAE），特别是棕榈酰乙醇酰胺（PEA）降解的关键酶之一。NAAA的药理学阻断恢复PEA水平，在炎症和疼痛的管理中提供治疗益处。本文对吡咯烷酰胺类NAAA抑制剂的构效关系进行了研究。研究了一系列吡咯烷酰胺末端苯基的芳族取代或取代。SAR数据显示，小的亲脂性3-苯基取代基对于最佳效力是优选的。构象灵活的接头增加了吡咯烷酰胺衍生物的抑制效力，但降低了它们对脂肪酸酰胺水解酶（FAAH）的选择性。构象限制性连接子没有增强对NAAA的抑制剂效力，但提高了对FAAH的选择性。开发了几种低微摩尔有效的NAAA抑制剂，包括带有刚性4-苯基肉桂酰基的4g。透析和动力学分析表明，4g通过竞争和可逆的机制抑制NAAA。4g对脂多糖（LPS）诱导的急性肺损伤（ALI）模型有明显的抗炎作用，该作用可被PPAR-α拮抗剂MK 886阻断。我们预计4g（E93）将成为一种治疗炎症和相关疾病的新药物。
N-Acylethanolamine acid amidase (NAAA) is one of the key enzymes involved in the degradation of fatty acid ethanolamides (FAEs), especially for palmitoylethanolamide (PEA). Pharmacological blockage of NAAA restores PEA levels, providing therapeutic benefits in the management of inflammation and pain. In the current work, we showed the structure–activity relationship (SAR) studies for pyrrolidine amide derivatives as NAAA inhibitors. A series of aromatic replacements or substituents for the terminal phenyl group of pyrrolidine amides were examined. SAR data showed that small lipophilic 3-phenyl substituents were preferable for optimal potency. The conformationally flexible linkers increased the inhibitory potency of pyrrolidine amide derivatives but reduced their selectivity toward fatty acid amide hydrolase (FAAH). The conformationally restricted linkers did not enhance the inhibitor potency toward NAAA but improved the selectivity over FAAH. Several low micromolar potent NAAA inhibitors were developed, including 4g bearing a rigid 4-phenylcinnamoyl group. Dialysis and kinetic analysis suggested that 4g inhibited NAAA via a competitive and reversible mechanism. Furthermore, 4g showed high anti-inflammatory activities in lipopolysaccharide (LPS) induced acute lung injury (ALI) model, and this effect was blocked by pre-treatment with the PPAR-α antagonist MK886. We anticipate that 4g (E93) will enable a new agent to treat inflammation and related diseases.