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

• Published in: Bioorganic & medicinal chemistry letters 2015-01, Vol.25 (2), p.372-377
• Main Authors: 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: Article
• Language: English
• Subjects: 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
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.11.029

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.