Discovery and optimization of a series of liver X receptor antagonists.
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.
Department of Medicinal Chemistry, Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, USA. xjiao@amgen.com
XianYun
X
Jiao
David J
DJ
Kopecky
Ben
B
Fisher
Derek E
DE
Piper
Marc
M
Labelle
Sharon
S
McKendry
Martin
M
Harrison
Stuart
S
Jones
Juan
J
Jaen
Andrew K
AK
Shiau
Patrick
P
Escaron
Jean
J
Danao
Anne
A
Chai
Peter
P
Coward
Frank
F
Kayser
D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008024:Ligands; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D015394:Molecular Structure; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000096926:Benzenesulfonamides
D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat