Discovery of 2,3'-diindolylmethanes as a novel class of PCSK9 modulators.
Discovery of 2,3'-diindolylmethanes as a novel class of PCSK9 modulators.
复制标题
发现 2,3-二吲哚基甲烷作为一类新型 PCSK9 调节剂。
DOI：
10.1016/j.bmcl.2019.06.014
复制
发表时间：
2019
影响因子：
2.7
通讯作者：
Tang,Weiping
中科院分区：
文献类型：
--
作者：
Winston-McPherson,GabrielleN;Xie,Haibo;Yang,Ka;Li,Xiaoxun;Shu,Dongxu;Tang,Weiping
蛋白转化酶subtilisin/ keexin type 9 （PCSK9）促进低密度脂蛋白受体（LDLR）的降解。抗pcsk9药物已被批准用于治疗高胆固醇血症。我们最近发现了一系列小分子PCSK9调节剂，其中含有相对较小的2,3 ' -二吲哚基甲烷药效团，分子量仅为250左右。在基于细胞的表型分析中，这些分子可以显著降低PCSK9蛋白的含量。我们的SAR研究得到了ic50值为200 nM的化合物16。浓度低于50 µM时未见明显细胞毒性。
Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of low density lipoprotein receptor (LDLR). Anti-PCSK9 agents have been approved for the treatment of hypercholesterolemia. We recently discovered a series of small-molecule PCSK9 modulators that contains a relatively small pharmacophore of 2,3′-diindolylmethane with molecular weights around only 250. These molecules can significantly lower the amount of PCSK9 protein in a cell-based phenotypic assay. Our SAR studies yielded compound16with a IC50-value of 200 nM. No obvious cytotoxicity was observed at concentrations below 50 µM.