Synthesis of 4-(3-biaryl)quinoline sulfones as potent liver X receptor agonists

A series of 4-(3-biaryl)quinolines with sulfone substituents on the terminal aryl ring (8) was prepared as potential LXR agonists. High affinity LXRβ ligands with generally modest binding selectivity over LXRα and excellent agonist potency in LXR functional assays were identified. Many compounds had LXRβ binding IC50 values <10 nM while the most potent had EC50 values <1.0 nM in an ABCA1 mRNA induction assay in J774 mouse cells with efficacy comparable to T0901317. Sulfone 8a was further evaluated in LDL (−/−) mice and shown to reduce atherosclerotic lesion progression.

Graphical abstractA series of 4-(3-biaryl)quinoline sulfones was prepared. High affinity LXRβ ligands with generally modest binding selectivity over LXRα and excellent agonist potency in LXR functional assays were identified.Figure optionsDownload full-size imageDownload as PowerPoint slide