Chemical Sciences, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426, USA.
Bioorg Med Chem. 2009 Dec 1;17(23):8086-92. doi: 10.1016/j.bmc.2009.10.001. Epub 2009 Oct 4.
A series of 4-(3-aryloxyaryl)quinolines with alcohol substituents on the terminal aryl ring was prepared as potential LXR agonists, in which an alcohol group replaced an amide in previously reported amide analogs. High affinity LXR ligands with excellent agonist potency and efficacy in a functional model of LXR activity were identified, demonstrating that alcohols can substitute for amides while retaining LXR activity. The most potent compound was 5b which had an IC(50)=3.3 nM for LXRbeta binding and EC(50)=12 nM (122% efficacy relative to T0901317) in an ABCA1 mRNA induction assay in J774 mouse cells.
我们制备了一系列带有末端芳基环上醇取代基的 4-(3-芳氧基芳基)喹啉，作为潜在的 LXR 激动剂，其中醇取代了先前报道的酰胺类似物中的酰胺。在 LXR 活性的功能模型中，我们鉴定出具有高亲和力和优异激动活性的 LXR 配体，证明醇可以取代酰胺而保持 LXR 活性。最有效的化合物是 5b，其在 J774 小鼠细胞中的 ABCA1 mRNA 诱导测定中对 LXRβ结合的 IC50=3.3 nM，EC50=12 nM（相对于 T0901317 的 122%功效）。
