Biarylether amide quinolines as liver X receptor agonists.
A series of 4-(amido-biarylether)-quinolines was prepared as potential LXR agonists. Appropriate substitution with amide groups provided high affinity LXR ligands, some with excellent potency and efficacy in functional assays of LXR activity. Novel amide 4g had a binding IC(50)=1.9 nM for LXRbeta and EC(50)=34 nM (96% efficacy relative to T0901317) in an ABCA1 gene expression assay in mouse J774 cells, demonstrating that 4-(biarylether)-quinolines with appropriate amide substitution are potent LXR agonists.
Bernotas
Ronald C
RC
Chemical and Screening Sciences, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426, USA. bernotr@wyeth.com
Singhaus
Robert R
RR
Kaufman
David H
DH
Ullrich
John
J
Fletcher
Horace
H
Quinet
Elaine
E
Nambi
Ponnal
P
Unwalla
Rayomand
R
Wilhelmsson
Anna
A
Goos-Nilsson
Annika
A
Farnegardh
Mathias
M
Wrobel
Jay
J
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000737:chemistry / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D007700:Kinetics; D008024:Ligands; D000071518:Liver X Receptors; D051379:Mice; D008958:Models, Molecular; D057093:Orphan Nuclear Receptors; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000737:chemistry / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000577:Amides; D004268:DNA-Binding Proteins; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011804:Quinolines; D018160:Receptors, Cytoplasmic and Nuclear