Identification of phenylsulfone-substituted quinoxaline (WYE-672) as a tissue selective liver X-receptor (LXR) agonist.
A series of phenyl sulfone substituted quinoxaline were prepared and the lead compound 13 (WYE-672) was shown to be a tissue selective LXR Agonist. Compound 13 demonstrated partial agonism for LXRbeta in kidney HEK-293 cells but did not activate Gal4 LXRbeta fusion proteins in huh-7 liver cells. Although 13 showed potent binding affinity to LXRbeta (IC(50) = 53 nM), it had little binding affinity for LXRalpha (IC(50) > 1.0 microM) and did not recruit any coactivator/corepressor peptides in the LXRalpha multiplex assay. However, compound 13 showed good agonism in THP-1 cells with respect to increasing ABCA1 gene expression and good potency on cholesterol efflux in THP-1 foam cells. In an eight-week lesion study in LDLR -/- mice, compound 13 showed reduction of aortic arch lesion progression and no plasma or hepatic triglyceride increase. These results suggest quinoxaline 13 may have an improved biological profile for potential use as a therapeutic agent.
Hu
Baihua
B
Chemical Sciences, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. bhu519@aol.com
Unwalla
Rayomand J
RJ
Goljer
Igor
I
Jetter
James W
JW
Quinet
Elaine M
EM
Berrodin
Thomas J
TJ
Basso
Michael D
MD
Feingold
Irene B
IB
Nilsson
Annika Goos
AG
Wilhelmsson
Anna
A
Evans
Mark J
MJ
Wrobel
Jay E
JE
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000818:Animals; D019540:Area Under Curve; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D004386:Duodenum / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D009928:Organ Specificity; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000235:genetics; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015533:Transcriptional Activation; D014280:Triglycerides / Q000378:metabolism
C549345:3-methyl-2-(3'-(methylsulfonyl)biphenyl-4-yl)-5-(trifluoromethyl)quinoxaline; C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D011810:Quinoxalines; D013450:Sulfones; D014280:Triglycerides; D002784:Cholesterol