title: The discovery of tertiary-amine LXR agonists with potent cholesterol efflux activity in macrophages.
abstract: 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.
authors.affiliation: 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
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Marino
authors.forename: Lara S
authors.initials: LS
authors.lastname: Kallander
authors.forename: Chun
authors.initials: C
authors.lastname: Ma
authors.forename: Hye-Ja
authors.initials: HJ
authors.lastname: Oh
authors.forename: Dennis
authors.initials: D
authors.lastname: Lee
authors.forename: Dimitri E
authors.initials: DE
authors.lastname: Gaitanopoulos
authors.forename: John A
authors.initials: JA
authors.lastname: Krawiec
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Parks
authors.forename: Christine L
authors.initials: CL
authors.lastname: Webb
authors.forename: Kelly
authors.initials: K
authors.lastname: Ziegler
authors.forename: Michael
authors.initials: M
authors.lastname: Jaye
authors.forename: Scott K
authors.initials: SK
authors.lastname: Thompson
mesh_terms: 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
chemical_list: D000588:Amines; D001057:Apolipoproteins E; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D002784:Cholesterol