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 LXR in a cell-free ligand-sensing assay with an EC50 of 125 nM and profiles as a full agonist on hLXR and hLXR 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.
Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines
Collins, JL., Fivush, AM., Watson, MA., Galardi, CM., Lewis, MC., Moore, LB., ... Wilson, A. (2002). Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. Journal of Medicinal Chemistry, 45(10), 1963-1966.