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

Jon L. Collins, Jane G. Binz, Kelli D. Plunket, Daniel G. Morgan, Elizabeth J. Beaudet, Karl D. Whitney, Steven A. Kliewer, Timothy M. Willson, Adam M. Fivush, Michael A. Watson, Cristin M. Galardi, Michael C. Lewis, Linda B. Moore, Derek J. Parks, Joan G. Wilson, Tim K. Tippin

Research output: Contribution to journalArticle

336 Scopus citations

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 LXRα in a cell-free ligand-sensing assay with an EC50 of 125 nM and profiles as a full agonist on hLXRα and hLXRβ in cell-based reporter gene assays with EC50'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.

Original languageEnglish (US)
Pages (from-to)1963-1966
Number of pages4
JournalJournal of Medicinal Chemistry
Volume45
Issue number10
DOIs
StatePublished - May 9 2002

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Collins, J. L., Binz, J. G., Plunket, K. D., Morgan, D. G., Beaudet, E. J., Whitney, K. D., Kliewer, S. A., Willson, T. M., Fivush, A. M., Watson, M. A., Galardi, C. M., Lewis, M. C., Moore, L. B., Parks, D. J., Wilson, J. G., & Tippin, T. K. (2002). Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. Journal of Medicinal Chemistry, 45(10), 1963-1966. https://doi.org/10.1021/jm0255116