N-Acylthiadiazolines, a new class of liver X receptor agonists with selectivity for LXRbeta.
We have identified a novel liver X receptor (LXR) agonist (2) that activates the LXRbeta subtype with selectivity over LXRalpha. LXRbeta selectivity was confirmed using macrophages derived from LXR mutant mice. Despite its selectivity and modest potency, the compound can induce APO-AI-dependent cholesterol efflux from macrophages with full efficacy. Our results indicate that it is possible to achieve significant LXRbeta selectivity in a small molecule while maintaining functional LXR activity.
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA. vmolteni@gnf.org
Valentina
V
Molteni
Xiaolin
X
Li
Juliet
J
Nabakka
Fang
F
Liang
John
J
Wityak
Alan
A
Koder
Leo
L
Vargas
Russell
R
Romeo
Nico
N
Mitro
Puiying A
PA
Mak
H Martin
HM
Seidel
Jennifer A
JA
Haslam
Donald
D
Chow
Tove
T
Tuntland
Tracy A
TA
Spalding
Ansgar
A
Brock
Michelle
M
Bradley
Antonio
A
Castrillo
Peter
P
Tontonoz
Enrique
E
Saez
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000818:Animals; D016632:Apolipoprotein A-I / Q000494:pharmacology; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000071518:Liver X Receptors; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C523825:5-(4-chlorophenyl)-3-(2,4,6-trifluorophenyl)-2,3-dihydro-2-(2,3-dimethoxyphenyl)-1,3,4-thiadiazole; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013830:Thiadiazoles; D002784:Cholesterol