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 chol...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2007-08, Vol.50 (17), p.4255-4259
Main Authors: Molteni, Valentina, Li, Xiaolin, Nabakka, Juliet, Liang, Fang, Wityak, John, Koder, Alan, Vargas, Leo, Romeo, Russell, Mitro, Nico, Mak, Puiying A, Seidel, H Martin, Haslam, Jennifer A, Chow, Donald, Tuntland, Tove, Spalding, Tracy A, Brock, Ansgar, Bradley, Michelle, Castrillo, Antonio, Tontonoz, Peter, Saez, Enrique
Format: Article
Language:English
Subjects:
Animals
Apolipoprotein A-I - pharmacology
ATP Binding Cassette Transporter 1
ATP-Binding Cassette Transporters - biosynthesis
Cell Line
Cholesterol - metabolism
Crystallography, X-Ray
DNA-Binding Proteins - agonists
DNA-Binding Proteins - genetics
Hepatocytes - drug effects
Hepatocytes - metabolism
Humans
Liver X Receptors
Macrophages, Peritoneal - drug effects
Macrophages, Peritoneal - metabolism
Mice
Mice, Knockout
Orphan Nuclear Receptors
Receptors, Cytoplasmic and Nuclear - agonists
Receptors, Cytoplasmic and Nuclear - genetics
Stereoisomerism
Structure-Activity Relationship
Thiadiazoles - chemical synthesis
Thiadiazoles - chemistry
Thiadiazoles - pharmacology
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Summary: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.
ISSN:0022-2623