Identification of a Nonsteroidal Liver X Receptor Agonist through Parallel Array Synthesis of Tertiary Amines

• Published in: Journal of medicinal chemistry Vol. 45; no. 10; pp. 1963 - 1966
• Main Authors: Collins, Jon L, Fivush, Adam M, Watson, Michael A, Galardi, Cristin M, Lewis, Michael C, Moore, Linda B, Parks, Derek J, Wilson, Joan G, Tippin, Tim K, Binz, Jane G, Plunket, Kelli D, Morgan, Daniel G, Beaudet, Elizabeth J, Whitney, Karl D, Kliewer, Steven A, Willson, Timothy M
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.05.2002; Amer Chemical Soc
• Subjects: Administration, Oral; Amines - chemical synthesis; Amines - chemistry; Amines - pharmacology; Animals; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters - metabolism; Biological and medical sciences; Biological Availability; Cell-Free System; Chemistry, Medicinal; Cholesterol - metabolism; Cholesterol, HDL - blood; DNA-Binding Proteins; General and cellular metabolism. Vitamins; Genes, Reporter; Humans; Intestine, Small - metabolism; Life Sciences & Biomedicine; Liver X Receptors; Macrophages - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Orphan Nuclear Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Retinoic Acid - agonists; Receptors, Thyroid Hormone - agonists; Science & Technology; Structure-Activity Relationship; Up-Regulation; TANGIER-DISEASE; ABC1; CHOLESTEROL EFFLUX; RXR HETERODIMERS; BINDING CASSETTE TRANSPORTER-1; MUTATIONS; LXR-ALPHA; DEFICIENCY; HIGH-DENSITY-LIPOPROTEIN; OXYSTEROLS; Agonist; Nuclear receptor; Biological transport; Rodentia; Oral administration; Aminoether; Bioavailability; In vitro; Cholesterol; Dose activity relation; In vivo; Vertebrata; Mammalia; Structure activity relation; Mouse; Carboxylic acid; Animal; Chlorine Organic compounds; Benzenic compound; Pharmacokinetics; Chemical synthesis; Non steroid compound
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0255116

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.