Identification of Phenylsulfone-Substituted Quinoxaline (WYE-672) as a Tissue Selective Liver X-receptor (LXR) Agonist
| Autor: | Baihua Hu, Elaine Quinet, Irene Feingold, Igor Goljer, Thomas J. Berrodin, Mark J. Evans, James W Jetter, Jay Wrobel, Rayomand J. Unwalla, Michael D Basso, Annika Goos Nilsson, Anna Wilhelmsson |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Male
Models Molecular Transcriptional Activation Agonist Duodenum medicine.drug_class Pharmacology Kidney Cell Line Sulfone Mice Radioligand Assay Structure-Activity Relationship chemistry.chemical_compound Quinoxaline Quinoxalines Drug Discovery Coactivator medicine Animals Humans Structure–activity relationship Sulfones Liver X receptor Triglycerides Liver X Receptors Mice Knockout Chemistry Kidney metabolism Atherosclerosis Orphan Nuclear Receptors Mice Inbred C57BL Cholesterol Liver Biochemistry Organ Specificity Cell culture Area Under Curve Molecular Medicine ATP-Binding Cassette Transporters lipids (amino acids peptides and proteins) ATP Binding Cassette Transporter 1 Half-Life |
| Zdroj: | Journal of Medicinal Chemistry. 53:3296-3304 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm100034x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|