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., Parks, DJ., Wilson, JG., Tippin, TK., Binz, JG., Plunket, KD., Morgan, DG., Beaudet, EJ., Whitney, K., Kliewer, SA., & 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. http://pubs.acs.org/cgi-bin/abstract.cgi/jmcmar/2002/45/i10/abs/jm0255116.html