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

A series of quinoline-3-carboxamide containing sulfones was prepared and found to have good binding affinity for LXRβ and moderate binding selectivity over LXRα. The 8-Cl quinoline analog 33 with a high TPSA score, displayed 34-fold binding selectivity for LXRβ over LXRα (LXRβ IC50 = 16 nM), good activity for inducing ABCA1 gene expression in a THP macrophage cell line, desired weak potency in the LXRα Gal4 functional assay, and low blood–brain barrier penetration in rat.

Graphical abstractQuinoline 33 is a potent LXR agonist with binding selectivity for LXRβ and low blood–brain penetration.Figure optionsDownload full-size imageDownload as PowerPoint slide