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)

• Record Type: Journal Article
• Authors: Koura, Minoru; Yamaguchi, Yuki; Kurobuchi, Sayaka; Sumida, Hisashi; Watanabe, Yuichiro; Enomoto, Takashi; Matsuda, Takayuki; Okuda, Ayumu; Koshizawa, Tomoaki; Matsumoto, Yuki; Shibuya, Kimiyuki
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 16(2016)
• Page Start: 3436
• Page End: 3446
• Publication Date: 2016-08-15
• Subjects: Liver X receptor (LXR) β-selective -- 2-Hydroxyacetophenone -- ABCA1 -- HDL-C -- Anti-atherosclerosis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.05.048
• Languages: English
• ISSNs: 0968-0896

Abstract

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.