Discovery and optimization of a novel series of liver X receptor-alpha agonists.
A novel series of hexafluorocarbinols were discovered as potent activators of the liver X receptor-alpha using a fluorescence polarization assay. Structure-activity relationship study led to the identification of compounds that are more potent agonists than the endogenous ligand, 24(S), 25-epoxycholesterol, with similar efficacy. Several compounds, including T0901317, were shown to have desirable pharmacokinetic profiles suitable for in vivo studies.
Li
Leping
L
Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. leping1@amgen.com
Liu
Jiwen
J
Zhu
Liusheng
L
Cutler
Serena
S
Hasegawa
Hirohiko
H
Shan
Bei
B
Medina
Julio C
JC
D000284:Administration, Oral; D000818:Animals; D002784:Cholesterol / Q000031:analogs & derivatives / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000819:agonists*; D005454:Fluorescence Polarization; D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D000071518:Liver X Receptors; D008297:Male; D015394:Molecular Structure; D057093:Orphan Nuclear Receptors; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D002784:Cholesterol; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; C000605215:Nr1h3 protein, rat; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C028358:24,25-epoxycholesterol