Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines.
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.
Collins
Jon L
JL
Fivush
Adam M
AM
Watson
Michael A
MA
Galardi
Cristin M
CM
Lewis
Michael C
MC
Moore
Linda B
LB
Parks
Derek J
DJ
Wilson
Joan G
JG
Tippin
Tim K
TK
Binz
Jane G
JG
Plunket
Kelli D
KD
Morgan
Daniel G
DG
Beaudet
Elizabeth J
EJ
Whitney
Karl D
KD
Kliewer
Steven A
SA
Willson
Timothy M
TM
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000284:Administration, Oral; D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D002474:Cell-Free System; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D004268:DNA-Binding Proteins; D017930:Genes, Reporter; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D018168:Receptors, Retinoic Acid / Q000819:agonists*; D011988:Receptors, Thyroid Hormone / Q000819:agonists*; D013329:Structure-Activity Relationship; D015854:Up-Regulation
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000588:Amines; D008076:Cholesterol, HDL; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D002784:Cholesterol