Liver X receptor (LXR) partial agonists: biaryl pyrazoles and imidazoles displaying a preference for LXRβ

A series of biaryl pyrazole and imidazole Liver X Receptor (LXR) partial agonists has been synthesized displaying LXRβ selectivity. The LXRβ selective partial agonist 18 was identified with potent induction of ATP binding transporters ABCA1 and ABCG1 in human whole blood (EC50=1.2μM, 55% efficacy)....

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2015-01, Vol.25 (2), p.372-377
Hauptverfasser:	Kick, Ellen, Martin, Richard, Xie, Yinong, Flatt, Brenton, Schweiger, Edwin, Wang, Tie-Lin, Busch, Brett, Nyman, Michael, Gu, Xiao-Hui, Yan, Grace, Wagner, Brandee, Nanao, Max, Nguyen, Lam, Stout, Thomas, Plonowski, Artur, Schulman, Ira, Ostrowski, Jacek, Kirchgessner, Todd, Wexler, Ruth, Mohan, Raju
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals ATP Binding Cassette Transporter 1 - blood Drug Partial Agonism Humans Imidazoles - chemistry Imidazoles - pharmacokinetics Imidazoles - pharmacology Liver - drug effects Liver - metabolism Liver X Receptors Mice Models, Molecular Molecular Structure Orphan Nuclear Receptors - agonists Plasma - chemistry Pyrazoles - chemistry Pyrazoles - pharmacokinetics Pyrazoles - pharmacology Structure-Activity Relationship Sulfones - chemistry Sulfones - pharmacokinetics Sulfones - pharmacology Tissue Distribution Triglycerides - metabolism
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Beschreibung
Zusammenfassung:	A series of biaryl pyrazole and imidazole Liver X Receptor (LXR) partial agonists has been synthesized displaying LXRβ selectivity. The LXRβ selective partial agonist 18 was identified with potent induction of ATP binding transporters ABCA1 and ABCG1 in human whole blood (EC50=1.2μM, 55% efficacy). In mice 18 displayed peripheral induction of ABCA1 at 3 and 10mpk doses with no significant elevation of plasma or hepatic triglycerides at these doses, showing an improved profile compared to a full pan-agonist.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2014.11.029