Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines

  • J Med Chem. 2002 May 9;45(10):1963-6. doi: 10.1021/jm0255116.
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 M Willson
PMID: 11985463 DOI: 10.1021/jm0255116
Abstract

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.

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