Substituted benzamides containing azaspiro rings as upregulators of apolipoprotein A-I transcription.
Apolipoprotein A-I (Apo A-I) is the principal protein component of high density lipoprotein (HDL), which is generally considered as a potential therapeutic target against atherosclerosis. The understanding of the Apo A-I regulation mechanism has fuelled the development of novel HDL targeted therapeutic approaches. To identify novel agents that can upregulate Apo A-I expression, we performed a cell-based reporter assay to screen 25,600 small molecules. Based on the dataset obtained from screening, a series of novel analogs of substituted benzamides containing azaspiro rings were assessed for their ability to induce the transcription of the Apo A-I gene, and the structure-activity relationship (SAR) around these analogs was also proposed. The results indicated that the trifluoromethyl substituted benzamide containing an azaspiro ring is a promising backbone for designing Apo A-I transcriptional upregulator and could be viable leads for development of new drugs to prevent and treat atherosclerosis in the future.
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Yu
Y
Du
Yuan
Y
Yang
Wei
W
Jiang
Li
L
Wang
Xiao-Jian
XJ
Jia
Shu-Yi
SY
Si
Xiao-Fang
XF
Chen
Bin
B
Hong
D016632:Apolipoprotein A-I / Q000235:genetics*; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D006801:Humans; D054852:Small Molecule Libraries; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D016632:Apolipoprotein A-I; D001549:Benzamides; D054852:Small Molecule Libraries; D013141:Spiro Compounds