The discovery of tertiary-amine LXR agonists with potent cholesterol efflux activity in macrophages.
The liver X receptors (LXR) play a key role in cholesterol homeostasis and lipid metabolism. SAR studies around tertiary-amine lead molecule 2, an LXR full agonist, revealed that steric and conformational changes to the acetic acid and propanolamine groups produce dramatic effects on agonist efficacy and potency. The new analogs possess good functional activity, demonstrating the ability to upregulate LXR target genes, as well as promote cholesterol efflux in macrophages.
Marino
Joseph P
JP
Chemistry, Metabolic Pathways Centre for Excellence in Drug Discovery, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, United States. joseph.p.marino@gsk.com
Kallander
Lara S
LS
Ma
Chun
C
Oh
Hye-Ja
HJ
Lee
Dennis
D
Gaitanopoulos
Dimitri E
DE
Krawiec
John A
JA
Parks
Derek J
DJ
Webb
Christine L
CL
Ziegler
Kelly
K
Jaye
Michael
M
Thompson
Scott K
SK
D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D000588:Amines; D001057:Apolipoproteins E; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D002784:Cholesterol