4-(3-aryloxyaryl)quinoline alcohols are liver X receptor 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 LXRbeta binding and EC(50)=12 nM (122% efficacy relative to T0901317) in an ABCA1 mRNA induction assay in J774 mouse cells.
Chemical Sciences, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426, USA. bernotr@wyeth.com
Ronald C
RC
Bernotas
David H
DH
Kaufman
Robert R
RR
Singhaus
John
J
Ullrich
Rayomand
R
Unwalla
Elaine
E
Quinet
Ponnal
P
Nambi
Anna
A
Wilhelmsson
Annika
A
Goos-Nilsson
Jay
J
Wrobel
D000438:Alcohols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000502:physiology; D002460:Cell Line; D000071518:Liver X Receptors; D008264:Macrophages; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008958:Models, Molecular; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism*; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000438:Alcohols; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011804:Quinolines