Importance of the field: Liver X receptors (LXRs) are ligand activated transcription factors involved in cholesterol metabolism, glucose homeostasis, inflammation and lipogenesis. With the important physiological role of LXRs in reverse cholesterol transport (RCT), atherosclerosis is the best investigated therapeutic indication. While atherosclerosis is not yet clinically validated, Wyeth's LXRalpha/beta agonist LXR-623 indicated the key LXR target genes involved in RCT (ABCA1 and ABCG1) are upregulated in peripheral blood cells in a dose-dependent manner. While discontinued for CNS safety concerns, investigation of LXR-623 supports atherosclerosis as a clinical indication, and the possibility of identifying LXR agonists with profiles that avoid the strong lipogenic effects of full LXRalpha/beta agonists.
Areas covered in this review: Patents for LXR agonists from late 2006 up to August 2009 with emphasis on chemical matters and relationship to earlier disclosures, the biological data associated with selected analogues and therapeutic indications.
What the reader will gain: An overview of the majority of LXR scaffolds with representative structure activity relationships as well as the companies that are the chief players in the field.
Take home message: The future application of LXR agonists depends upon the discovery of LXR agents without lipogenic effects. Limiting activation of LXRalpha is a popular strategy.