2-Aryl-N-acyl indole derivatives as liver X receptor (LXR) agonists

Structure–activity relationship studies on a series of Boc-indole derivatives as LXR agonists are described. Compound 1 was identified as an LXR agonist through structure-based virtual screening followed by high-throughput gene profiling. Replacement of the indan linker portion in 1 with an open-chain linker resulted in compounds with similar or improved in vitro potency and cellular functional activity. The Boc group at the N-1 position of the indole moiety can be replaced with a benzoyl group. The SAR studies led to the identification of compound 8, a potent LXRβ agonist with an EC50 of 12 nM in the cofactor recruitment assay.

Graphical abstractSAR studies on HTS hit compound 1 led to the identification of simpler 2-aryl-1-acyl compounds such as 8 which are potent LXRβ agonists.Figure optionsDownload full-size imageDownload as PowerPoint slide