1. Academic Validation
  2. Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines

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
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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