Discovery of a 2-hydroxyacetophenone derivative as an outstanding linker to enhance potency and β-selectivity of liver X receptor agonist. Issue 16 (15th August 2016) - Koura, Minoru
Graphical abstract: Abstract: Our research found that the 2-hydroxyacetophenone derivative is an outstanding linker between the 1, 1-bistrifluoromethylcarbinol moiety and the imidazolidine-2, 4-dione moiety to enhance the potency and β-selectivity of liver X receptor (LXR) agonist in our head-to-tail molecular design. The incorporation of this linker is 20-fold more potent than our previous compound (2 ) for LXR β agonistic activity (EC50 ) in a GAL-4 luciferase assay. Furthermore, we also identified 5-[5-(1-methylethoxy)pyridyl-2-yl]-5-methylimidazoline-2, 4-dione (54 ), which lowers the lipophilicity of 2-hydroxyacetophenone derivative. We revealed that a combination of our newly developed linker and hydantoin (54 ) plays a pivotal role in improving the potency and selectivity of LXRβ. The optically separated (−)-56 increases high-density lipoprotein cholesterol levels without elevating plasma triglyceride levels and results in a decrease of the lipid accumulation area in the aortic arch in a high-fat- and cholesterol-fed low-density lipoprotein receptor knock-out mice. In this manuscript, we report that (−)-56 is a highly potent and β-selective LXR agonist for use in the treatment of atherosclerosis.