Quinoline-3-carboxamide containing sulfones as liver X receptor (LXR) agonists with binding selectivity for LXRb and low blood-brain penetration

A series of quinoline-3-carboxamide containing sulfones was prepared and found to have good binding affinity for LXRb and moderate binding selectivity over LXRa. The 8-Cl quinoline analog 33 with a high TPSA score, displayed 34-fold binding selectivity for LXRb over LXRa (LXRb IC sub(50) = 16 nM), g...

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Published in:Bioorganic & medicinal chemistry letters 2010-01, Vol.20 (2), p.689-693
Main Authors: Hu, Baihua, Bernotas, Ron, Unwalla, Rayomand, Collini, Michael, Quinet, Elaine, Feingold, Irene, Goos-Nilsson, Annika, Wilhelmsson, Anna, Nambi, Ponnal, Evans, Mark, Wrobel, Jay
Format: Article
Language:English
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Summary:A series of quinoline-3-carboxamide containing sulfones was prepared and found to have good binding affinity for LXRb and moderate binding selectivity over LXRa. The 8-Cl quinoline analog 33 with a high TPSA score, displayed 34-fold binding selectivity for LXRb over LXRa (LXRb IC sub(50) = 16 nM), good activity for inducing ABCA1 gene expression in a THP macrophage cell line, desired weak potency in the LXRa Gal4 functional assay, and low blood-brain barrier penetration in rat.
ISSN:0960-894X
DOI:10.1016/j.bmcl.2009.11.062