Structure-guided design of N-phenyl tertiary amines as transrepression-selective liver X receptor modulators with anti-inflammatory activity.
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.
Chao
Esther Y
EY
GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, USA.
Caravella
Justin A
JA
Watson
Mike A
MA
Campobasso
Nino
N
Ghisletti
Serena
S
Billin
Andrew N
AN
Galardi
Cristin
C
Wang
Ping
P
Laffitte
Bryan A
BA
Iannone
Marie A
MA
Goodwin
Bryan J
BJ
Nichols
Jason A
JA
Parks
Derek J
DJ
Stewart
Eugene
E
Wiethe
Robert W
RW
Williams
Shawn P
SP
Smallwood
Angela
A
Pearce
Kenneth H
KH
Glass
Christopher K
CK
Willson
Timothy M
TM
Zuercher
William J
WJ
Collins
Jon L
JL
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
D000588:Amines; D000893:Anti-Inflammatory Agents; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear