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.
Molteni
Valentina
V
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA. vmolteni@gnf.org
Li
Xiaolin
X
Nabakka
Juliet
J
Liang
Fang
F
Wityak
John
J
Koder
Alan
A
Vargas
Leo
L
Romeo
Russell
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Mitro
Nico
N
Mak
Puiying A
PA
Seidel
H Martin
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Haslam
Jennifer A
JA
Chow
Donald
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Tuntland
Tove
T
Spalding
Tracy A
TA
Brock
Ansgar
A
Bradley
Michelle
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Castrillo
Antonio
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Tontonoz
Peter
P
Saez
Enrique
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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