Discovery of a 2-hydroxyacetophenone derivative as an outstanding linker to enhance potency and ß-selectivity of liver X receptor agonist.

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 ß-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 ß 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 LXRß. 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 ß-selective LXR agonist for use in the treatment of atherosclerosis.

Design, synthesis and pharmacology of 1,1-bistrifluoromethylcarbinol derivatives as liver X receptor ß-selective agonists.

A novel series of 1,3-bistrifluoromethylcarbinol derivatives that act as liver X receptor (LXR) ß-selective agonists was discovered. Structure-activity relationship studies led to the identification of molecule 62, which was more effective (Emax) and selective toward LXRß than T0901317 and GW3965. Furthermore, 62 decreased LDL-C without elevating the plasma TG level and significantly suppressed the lipid-accumulation area in the aortic arch in a Bio F1B hamster fed a diet high in fat and cholesterol. We demonstrated that our LXRß agonist would be potentially useful as a hypolipidemic and anti-atherosclerotic agent. In this manuscript, we report the design, synthesis and pharmacology of 1,3-bistrifluoromethylcarbinol derivatives.

Design and discovery of 2-oxochromene derivatives as liver X receptor ß-selective agonists.

In an attempt to molecularly design liver X receptor (LXR) ß-selective agonists, we discovered that the combination of the 2-oxochromene moiety (head) and the imidazoline-2,4-dione moiety (tail) plays an important role in the expression potency and selectivity toward LXRß. We synthesized a series of 2-oxochromene derivatives and identified 43 as a LXRß-selective agonist that increased the HDL-C level without significantly elevating the TG level and resulted in a decreased lipid-accumulation area in the aortic arch in a high-fat-and-cholesterol-fed Bio F1B hamster. In this manuscript, we report the design, synthesis and pharmacology of these 2-oxochromene derivatives.