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

doi:10.1016/j.bmcl.2014.11.029

Bioorganic & Medicinal Chemistry Letters

Volume 25, Issue 2, 15 January 2015, Pages 372-377

https://doi.org/10.1016/j.bmcl.2014.11.029 Get rights and content

Abstract

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 = 1.2 μM, 55% efficacy). In mice 18 displayed peripheral induction of ABCA1 at 3 and 10 mpk doses with no significant elevation of plasma or hepatic triglycerides at these doses, showing an improved profile compared to a full pan-agonist.

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Acknowledgments

The authors thank Joanne Molay for helping with preparation of molecules described herein. We thank Susan Zimmerman, Nhin Lu, Sihong Zhou, and Peter Ordentlich for their support on assay optimization and routine screening, as well as, Gang Shao, and Jay Hou for their contributions to the assay development. We thank Hangjun Zhan, Doug Buckley, Chris Bonagura, and Doug Yan for guidance and assistance with protein biochemistry and crystallography, Jodi Muckelbauer for preparing Figure 2 for

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

Abstract

Graphical abstract

Section snippets

Acknowledgments

J. Biol. Chem.

FEBS Lett.

Cell

J. Invest. Dermatol.

J. Lipid Res.

Biochem. Pharmacol.

J. Biol. Chem.

J. Lipid Res.

J. Lipid Res.

J. Biol. Chem.

Circulation

Nat. Med.

Curr. Top. Med. Chem.

Science

Arterioscler. Thromb. Vasc. Biol.

Proc. Natl. Acad. Sci. U.S.A.

Circulation

Gene Dev.