title: Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines.
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.
authors: Jon L
authors: JL
authors: Collins
authors: Adam M
authors: AM
authors: Fivush
authors: Michael A
authors: MA
authors: Watson
authors: Cristin M
authors: CM
authors: Galardi
authors: Michael C
authors: MC
authors: Lewis
authors: Linda B
authors: LB
authors: Moore
authors: Derek J
authors: DJ
authors: Parks
authors: Joan G
authors: JG
authors: Wilson
authors: Tim K
authors: TK
authors: Tippin
authors: Jane G
authors: JG
authors: Binz
authors: Kelli D
authors: KD
authors: Plunket
authors: Daniel G
authors: DG
authors: Morgan
authors: Elizabeth J
authors: EJ
authors: Beaudet
authors: Karl D
authors: KD
authors: Whitney
authors: Steven A
authors: SA
authors: Kliewer
authors: Timothy M
authors: TM
authors: Willson
mesh_terms: 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
chemical_list: 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