Identification of a Nonsteroidal Liver X Receptor Agonist through Parallel Array Synthesis of Tertiary Amines

作者：Jon L. Collins, Adam M. Fivush, Michael A. Watson, Cristin M. Galardi, Michael C. Lewis, Linda B. Moore, Derek J. Parks, Joan G. Wilson, Tim K. Tippin, Jane G. Binz, Kelli D. Plunket, Daniel G. Morgan, Elizabeth J. Beaudet, Karl D. Whitney, Steven A. Kliewer, Timothy Mark Willson · 发表于：Journal of Medicinal Chemistry · 年份：2002 · DOI：10.1021/jm0255116 · 被引用次数：437 · 研究领域：Cholesterol and Lipid Metabolism、Drug Transport and Resistance Mechanisms、Peroxisome Proliferator-Activated Receptors

A potent, selective, orally active LXR agonist was identified from focused libraries of tertiary amines. GW3965 (12) recruits the steroid receptor coactivator 1 to human LXRalpha in a cell-free ligand-sensing assay with an EC(50) of 125 nM and profiles as a full agonist on hLXRalpha and hLXRbeta in cell-based reporter gene assays with EC(50)'s of 190 and 30 nM, respectively. After oral dosing at 10 mg/kg to C57BL/6 mice, 12 increased expression of the reverse cholesterol transporter ABCA1 in the small intestine and peripheral macrophages and increased the plasma concentrations of HDL cholesterol by 30%. 12 will be a valuable chemical tool to investigate the role of LXR in the regulation of reverse cholesterol transport and lipid metabolism.