4-(3-Aryloxyaryl)quinoline alcohols are liver X receptor agonists

• Published in: Bioorganic & medicinal chemistry Vol. 17; no. 23; pp. 8086 - 8092
• Main Authors: Bernotas, Ronald C., Kaufman, David H., Singhaus, Robert R., Ullrich, John, Unwalla, Rayomand, Quinet, Elaine, Nambi, Ponnal, Wilhelmsson, Anna, Goos-Nilsson, Annika, Wrobel, Jay
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.12.2009; Elsevier
• Subjects: ABCA1; Alcohol; Alcohols - chemical synthesis; Alcohols - chemistry; Alcohols - pharmacology; Animals; Biarylether; Binding, Competitive - physiology; Biological and medical sciences; Cell Line; Hormones. Endocrine system; Liver X receptor; Liver X Receptors; LXR; Macrophages; Magnetic Resonance Spectroscopy; Mass Spectrometry; Medical sciences; Mice; Models, Molecular; Orphan Nuclear Receptors - agonists; Orphan Nuclear Receptors - metabolism; Pharmacology. Drug treatments; Quinoline; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; ABCA1; Liver X receptor; Quinoline; Alcohol; LXR; Biarylether; Agonist; Nuclear receptor; Modeling; Signal transduction; Structure activity relation; Tertiary alcohol; Molecular model; Chemical synthesis; Carrier protein; Ether; Rodentia; Benzene derivatives; Quinoline derivatives; Inhibitor enzyme complex; Gene expression; In vitro; Vertebrata; Mammalia; Cell line; Mouse; Affinity; Fluorine Organic compounds; ABC transporter; Macrophage; Hormonal receptor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.10.001

A series of 4-(3-aryloxyaryl)quinolines 5 was prepared as LXR agonists. A series of 4-(3-aryloxyaryl)quinolines with alcohol substituents on the terminal aryl ring was prepared as potential LXR agonists, in which an alcohol group replaced an amide in previously reported amide analogs. High affinity LXR ligands with excellent agonist potency and efficacy in a functional model of LXR activity were identified, demonstrating that alcohols can substitute for amides while retaining LXR activity. The most potent compound was 5b which had an IC 50 = 3.3 nM for LXRβ binding and EC 50 = 12 nM (122% efficacy relative to T0901317) in an ABCA1 mRNA induction assay in J774 mouse cells.