Recent progress in liver X receptor-selective modulators.

The liver X receptors LXRalpha and LXRbeta regulate the expression of genes promoting cellular cholesterol efflux and the formation of HDL particles, and are atheroprotective. However, LXRalpha and LXRbeta also regulate the expression of genes involved in lipogenesis and hypertriglyceridemia. The identification of efficacious LXR modulators that are devoid of undesirable side effects remains a significant challenge for drug development. The X-ray structures of many LXR protein/small-molecule complexes have revealed that the ligand-binding pockets of LXRalpha and LXRbeta, despite being highly conserved, are large and flexible; these properties have allowed the design of a wide range of ligands with varied selectivity profiles. This review discusses the latest medicinal chemistry strategies used to derive novel LXR modulators with the potential for enhanced therapeutic utility and safety, and summarizes the current status of compounds that have progressed into clinical development.