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

2014; Elsevier BV; Volume: 25; Issue: 2 Linguagem: Inglês

10.1016/j.bmcl.2014.11.029

1464-3405

Ellen K. Kick, Richard Martin, Yinong Xie, Brenton Flatt, Edwin J. Schweiger, Tielin Wang, Brett B. Busch, Michael C. Nyman, Xiao‐Hui Gu, Grace Yan, Brandee Wagner, Max Nanao, Lam Nguyen, Thomas J. Stout, Artur Płonowski, Ira G. Schulman, Jacek Ostrowski, Todd G. Kirchgessner, Ruth R. Wexler, Raju Mohan,

Sphingolipid Metabolism and Signaling

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.