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.
Bernotas
Ronald C
RC
Chemical Sciences, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426, USA. bernotr@wyeth.com
Kaufman
David H
DH
Singhaus
Robert R
RR
Ullrich
John
J
Unwalla
Rayomand
R
Quinet
Elaine
E
Nambi
Ponnal
P
Wilhelmsson
Anna
A
Goos-Nilsson
Annika
A
Wrobel
Jay
J
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