新型吲哚类胆固醇酯转运蛋白抑制剂的设计、合成及生物活性研究

Design,synthesis and biological evaluation of indole derivatives as novel cholesteryl ester transfer protein inhibitors

目的设计并合成一系列以吲哚为母核的新型小分子胆固醇酯转运蛋白(CETP)抑制剂,并初步评价其体外抑制活性。方法以实验室前期获得的化合物Ⅰ为先导化合物,主要对其吲哚母环的2,3,5位进行修饰改造。以吲哚-2-羧酸乙酯衍生物为原料,通过还原、氧化、还原胺化、取代、Suzuki偶联、亲核取代反应制备得到8个目标化合物;以吲哚或吲哚-2-羧酸乙酯为原料,经Vilsmeier反应在3位引入醛基,再经过还原胺化、取代、Suzuki偶联、亲核取代得到7个目标化合物;进一步通过对2位酯基水解或经还原、烷基化得到另外2个目标化合物。采用BODIPY-CE荧光分析法,以anacetrapib为阳性对照药,测试目标化合物体外对CETP的抑制活性。结果与结论合成了17个未见报道的新化合物,结构经~1H-NM R、M S、^(13)C-NM R谱确证;活性测试表明该类化合物具有中等强度的CETP抑制活性,其中化合物10h的活性较先导化合物有接近10倍的提高,为今后该类化合物的结构优化提供了重要指导。

CETP facilitates the movement of cholesteryl esters（CEs） from HDL to LDL and VLDL,which leads to lower levels of HDL-C. So developing high efficient and lowside effect CETP inhibitors will be another strategy in treatment of atherosclerotic cardiovascular disease. According to our previous study,we used compound Ⅰ as a lead compound for further optimization. Structure optimization was divided into two parts： Firstly,replacing the H atom by different substituent groups at the 5-position and 1-position. Furthermore,we moved the side chain from the 2-position to 3-position and modified the 1 and 2-positions of indole. Compounds 10 a-10 h were obtained via reduction,oxidation,reductive amination,substitution,Suzuki coupling reaction and nucleophilic substitution,using indol-2-carboxylic acid ethyl ester derivatives as starting material. Based on indole or ethyl indole-2-carboxylate,the formal group was introduced by Vilsmeier reaction. The aldehyde intermediates underwent reductive amination,substitution,Suzuki coupling reaction and nucleophilic substitution to provide compounds 15 a-15 g. The other two compounds（15h,15i） were obtained from compound 15 c. Seventeen compounds were obtained and all of the compounds have not been reported in literatures and their structures were confirmed by 1H-NMR,13C-NMR and MS. Utilizing the BODIPY-CE fluorometry,we obtained the in vitro activities of compounds. The results showed that compound 10 h had good inhibitory activity against CETP.