Discovery and SAR of cinnolines/quinolines as liver X receptor (LXR) agonists with binding selectivity for LXRbeta.
A series of cinnolines/quinolines was prepared and it was found that 4-phenyl-cinnoline/quinolines with either a 2',3' or 2',5'-disubstituted benzyloxy moiety or the 1-Me-7-indole methoxy moiety on the meta position of the 4-phenyl ring showed good binding selectivity for LXRbeta over LXRalpha. The LXRbeta binding selective modulators displayed good activity for inducing ABCA1 gene expression in J774 macrophage cell line and poor efficacy in the LXRalpha Gal4 functional assay. 26, 37 and 41 were examined for their ability to induce SREBP-1c gene expression in Huh-7 liver cell line and they were weak partial agonists.
Hu
Baihua
B
Chemical and Screening Science, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. hub@wyeth.com
Unwalla
Raymound
R
Collini
Michael
M
Quinet
Elaine
E
Feingold
Irene
I
Goos-Nilsson
Annika
A
Wihelmsson
Anna
A
Nambi
Ponnal
P
Wrobel
Jay
J
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000378:metabolism; D055808:Drug Discovery; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry*; D006801:Humans; D000071518:Liver X Receptors; D051379:Mice; D057093:Orphan Nuclear Receptors; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D013329:Structure-Activity Relationship
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; D006574:Heterocyclic Compounds, 2-Ring; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D011804:Quinolines; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; C476282:cinnoline