Dockendorff Chris, Faloon Patrick W, Germain Andrew, Yu Miao, Youngsaye Willmen, Nag Partha P, Bennion Melissa, Penman Marsha, Nieland Thomas J F, Dandapani Sivaraman, Perez José R, Munoz Benito, Palmer Michelle A, Schreiber Stuart L, Krieger Monty
Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA; Department of Chemistry, Marquette University, PO Box 1881, Milwaukee, WI 53201-1881, USA.
Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
Bioorg Med Chem Lett. 2015 Jun 15;25(12):2594-8. doi: 10.1016/j.bmcl.2015.03.074. Epub 2015 Apr 11.
A new series of potent inhibitors of cellular lipid uptake from HDL particles mediated by scavenger receptor, class B, type I (SR-BI) was identified. The series was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR) that measured the transfer of the fluorescent lipid DiI from HDL particles to CHO cells overexpressing SR-BI. The series is characterized by a linear peptidomimetic scaffold with two adjacent amide groups, as well as an aryl-substituted heterocycle. Analogs of the initial hit were rapidly prepared via Ugi 4-component reaction, and select enantiopure compounds were prepared via a stepwise sequence. Structure-activity relationship (SAR) studies suggest an oxygenated arene is preferred at the western end of the molecule, as well as highly lipophilic substituents on the central and eastern nitrogens. Compound 5e, with (R)-stereochemistry at the central carbon, was designated as probe ML279. Mechanistic studies indicate that ML279 stabilizes the interaction of HDL particles with SR-BI, and its effect is reversible. It shows good potency (IC50=17 nM), is non-toxic, plasma stable, and has improved solubility over our alternative probe ML278.
鉴定出了一系列新型强效抑制剂，它们可抑制由清道夫受体B类I型（SR-BI）介导的细胞从高密度脂蛋白（HDL）颗粒摄取脂质。该系列是通过美国国立卫生研究院分子文库小分子储存库（NIH MLSMR）的高通量筛选鉴定出来的，该筛选测量了荧光脂质DiI从HDL颗粒向过表达SR-BI的CHO细胞的转移。该系列的特征是具有两个相邻酰胺基团的线性拟肽支架以及芳基取代的杂环。通过Ugi四组分反应快速制备了初始命中物的类似物，并通过逐步序列制备了选定的对映体纯化合物。构效关系（SAR）研究表明，分子西端优选含氧芳烃，以及中央和东部氮上的高亲脂性取代基。在中心碳处具有（R）-立体化学的化合物5e被指定为探针ML279。机理研究表明，ML279可稳定HDL颗粒与SR-BI的相互作用，并且其作用是可逆的。它显示出良好的效力（IC50 = 17 nM），无毒，血浆稳定，并且与我们的替代探针ML278相比具有更好的溶解性。
