新型脂肪酰胺水解酶抑制剂的设计，合成和活性评价

Design, Synthesis and Enzyme Assay of Novel Fatty Acid Amide Hydrolase (FAAH) Inhibitors

关键词:  脂肪酰胺水解酶抑制剂  计算机辅助药物设计  合成  活性测定

Key words:  fatty acid amide inhibitors  computer-acid drug design  synthesis  enzyme assay

摘要:

摘要：目的 设计合成新型的脂肪酰胺水解酶(FAAH)抑制剂，并对其活性评价。 方法 通过已有FAAH酶抑制剂的结构和活性构建药效团模型，对部分ZINC数据库粗筛；通过与FAAH酶分子对接，对粗筛所获得的小分子化合物的活性进行打分评价并，确定拟合成目标化合物的母核结构(2-氧代苯并吡喃-7-酯)；采用酰化、缩合反应，合成系列目标化合物；通过体外酶抑制活性实验检测其活性。 结果 化合物(±)-2-(2-苯氧基乙酰基氨基)-丙酸-2-氧代苯并吡喃-7-酯(2b)的IC50值为95.24 μmol.L-1，(±)-1-(2-苯氧基-乙酰基)-吡咯烷-2-羧酸-2-氧代苯并吡喃-7-酯(2g)的IC50值为17.34μmol.L-1，具有较好的抑制FAAH酶活性的作用。 结论 本文活性化合物的结构与目前报道的脂肪酰胺水解酶抑制剂结构差异较大，有望成为新类型先导化合物。

Abstract:

ABSTRACT: OBJECTIVE To discover novel fatty acid amide hydrolase inhibitors and evaluate their enzymatic activity. METHODS The pharmacophore model was based on the compounds carefully selected from the published literatures. This model was used to screen part of ZINC Nature Products database to get a series of compounds which were used to do a superimposition analysis of the FAAH X-ray crystal structure. Through the virtual screening and the structure-activity analysis of the compouds published in the literatures, the hitting compound structure(2-oxygen-benzo pyran-7-ester) was selected to do the transformation. The acylation and condensation reactions were used to get a series of novel compounds. The enzymatic activity was tested by LC-MS in vitro. RESULTS Compounds (±)-2-(2-Phenoxy-acetylamino)-propionic acid 2-oxo-2H-chromen-7-yl ester(2b)(IC50 95.24 μmol.L-1)and (±)-1-(2-Phenoxy-acetyl)-pyrrolidine-2-carboxylic acid 2-oxo-2H-chromen-7-yl ester (2g)(IC50 17.34 μmol.L-1)showed good inhibition to FAAH in enzyme assay. CONCLUSION The compounds which had been discovered were different from other FAAH inhibitors and worthy of further study as a lead compound.