人膜转运蛋白ABCA1及清道夫受体CLA-1表达上调剂的筛选和活性研究  

Identification of up-regulators of ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor class B type Ⅰ(CLA-1)

作　　者：许艳妮[1] 李永臻[1] 李霓[1] 刘畅[1] 冯婷婷[1] 司书毅[1] 

机构地区：[1]中国医学科学院北京协和医学院医药生物技术研究所国家新药(微生物)筛选实验室,北京100050

出　　处：《中国医药生物技术》2013年第3期161-165,共5页Chinese Medicinal Biotechnology

基　　金：国家自然科学基金(81102443);国家自然科学基金面上项目(81273515)

摘　　要：目的筛选上调人ATP结合盒转运体A1(ABCA1)和人清道夫受体(CLA-1)表达的新型活性化合物,为抗动脉粥样硬化药物提供先导化合物。方法应用本实验室已经建立的ABCA1和CLA-1表达上调剂的高通量筛选模型对20000个化合物进行筛选,从中获得能上调ABCA1和CLA-1表达的化合物,对其及结构类似物进行活性测定,并进行初步的构效关系研究。结果化合物5033171和5242411具有较好的上调ABCA1和CLA-1表达的活性,在ABCA1上调剂模型上的EC50分别为2.10和3.87μmol/L,在CLA-1上调剂模型上的EC50分别为1.37和1.57μmol/L。构效关系研究结果提示苯并噻唑的6位有长链烷基取代对增加活性有利。结论化合物5033171和5242411是活性很好的ABCA1和CLA-1上调剂。Objective The aim of the study is to find new anti-atherosclerotic agents which can up-regulate human ATP-binding cassette transporter A 1 （ABCA 1） and scavenger receptor class B type I （CLA-l） expressions. Methods By using cell-based high throughput screening models for ABCA1 and CLA-1 up-regulators, a series of novel analogs of substituted N-（benzo[d]thiazol-2-yl）benzamide containing 3-（N-（2-cyanoethyl）sulfamoyl） were found and assessed for their abilities to induce the transcription of the ABCA 1 and CLA-1 genes. And the structure-activity relationship （SAR） around these analogs was also proposed. Results The series of novel analogs of substituted N-（benzo[d]thiazol-2-yl）-3-（N-（2-cyanoethyl）sulfamoyl） benzamide could induce the transcription of the ABCA 1 and CLA- 1 gene. The ECso value of compounds （5033171 and 5242411） in ABCA lp-LUC HepG2 cell was 2.10 and 3.87 p.mol/L, respectively. The ECs0 value of compounds （5033171 and 5242411） in CLA-lp-LUC HepG2 cell was 1.37 and 1.57 pmol/L, respectively. The preliminary SAR showed replacement the 6-substituent of benzo[d]thiazole with large alkyl led to increase of the activity among these compounds. Conclusion This is a first report showing that N-（benzo[d]thiazol-2-yl）benzamide containing 3-（N-（2-cyanoethyl）sulfamoyl） is a promising backbone for designing ABCA1 and CLA-1 transcriptional up-regulators and could be viable leads for development of new drugs to prevent and treat atherosclerosis in the future.

关 键 词：ATP结合匣式转运子 动脉粥样硬化 高通量筛选 

分 类 号：R543.5[医药卫生—心血管疾病]