Discovery and optimization of a series of liver X receptor antagonists

XianYun Jiao; David J Kopecky; Ben Fisher; Derek E Piper; Marc Labelle; Sharon McKendry; Martin Harrison; Stuart Jones; Juan Jaen; Andrew K Shiau; Patrick Escaron; Jean Danao; Anne Chai; Peter Coward; Frank Kayser

doi:10.1016/j.bmcl.2012.07.048

Discovery and optimization of a series of liver X receptor antagonists

Bioorg Med Chem Lett. 2012 Sep 15;22(18):5966-70. doi: 10.1016/j.bmcl.2012.07.048. Epub 2012 Jul 21.

Authors

XianYun Jiao¹, David J Kopecky, Ben Fisher, Derek E Piper, Marc Labelle, Sharon McKendry, Martin Harrison, Stuart Jones, Juan Jaen, Andrew K Shiau, Patrick Escaron, Jean Danao, Anne Chai, Peter Coward, Frank Kayser

Affiliation

¹ Department of Medicinal Chemistry, Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, USA. xjiao@amgen.com

PMID: 22901900
DOI: 10.1016/j.bmcl.2012.07.048

Abstract

The present report describes our efforts to convert an existing LXR agonist into an LXR antagonist using a structure-based approach. A series of benzenesulfonamides was synthesized based on structural modification of a known LXR agonist and was determined to be potent dual liver X receptor (LXR α/β) ligands. Herein we report the identification of compound 54 as the first reported LXR antagonist that is suitable for pharmacological in vivo evaluation in rodents.

MeSH terms

Animals
Benzenesulfonamides
Dose-Response Relationship, Drug
Drug Discovery*
HEK293 Cells
Hep G2 Cells
Humans
Ligands
Liver X Receptors
Male
Mice
Molecular Structure
Orphan Nuclear Receptors / antagonists & inhibitors*
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*

Substances

Ligands
Liver X Receptors
NR1H3 protein, human
Nr1h3 protein, mouse
Nr1h3 protein, rat
Orphan Nuclear Receptors
Sulfonamides