title: Structure-guided design of N-phenyl tertiary amines as transrepression-selective liver X receptor modulators with anti-inflammatory activity.
abstract: A cocrystal structure of T1317 (3) bound to hLXRbeta was utilized in the design of a series of substituted N-phenyl tertiary amines. Profiling in binding and functional assays led to the identification of LXR modulator GSK9772 ( 20) as a high-affinity LXRbeta ligand (IC 50 = 30 nM) that shows separation of anti-inflammatory and lipogenic activities in human macrophage and liver cell lines, respectively. A cocrystal structure of the structurally related analog 19 bound to LXRbeta reveals regions within the receptor that can affect receptor modulation through ligand modification. Mechanistic studies demonstrate that 20 is greater than 10-fold selective for LXR-mediated transrepression of proinflammatory gene expression versus transactivation of lipogenic signaling pathways, thus providing an opportunity for the identification of LXR modulators with improved therapeutic indexes.
authors.affiliation: GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Esther Y
authors.initials: EY
authors.lastname: Chao
authors.forename: Justin A
authors.initials: JA
authors.lastname: Caravella
authors.forename: Mike A
authors.initials: MA
authors.lastname: Watson
authors.forename: Nino
authors.initials: N
authors.lastname: Campobasso
authors.forename: Serena
authors.initials: S
authors.lastname: Ghisletti
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Billin
authors.forename: Cristin
authors.initials: C
authors.lastname: Galardi
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Laffitte
authors.forename: Marie A
authors.initials: MA
authors.lastname: Iannone
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Goodwin
authors.forename: Jason A
authors.initials: JA
authors.lastname: Nichols
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Parks
authors.forename: Eugene
authors.initials: E
authors.lastname: Stewart
authors.forename: Robert W
authors.initials: RW
authors.lastname: Wiethe
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Williams
authors.forename: Angela
authors.initials: A
authors.lastname: Smallwood
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Pearce
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Willson
authors.forename: William J
authors.initials: WJ
authors.lastname: Zuercher
authors.forename: Jon L
authors.initials: JL
authors.lastname: Collins
mesh_terms: D000588:Amines / Q000737:chemistry* / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000187:drug effects*; D015195:Drug Design; D000071518:Liver X Receptors; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D015394:Molecular Structure; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000893:Anti-Inflammatory Agents; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear