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

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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Koura M,Yamaguchi Y,Kurobuchi S,Sumida H,Watanabe Y,Enomoto T,Matsuda T,Okuda A,Koshizawa T,Matsumoto Y,Shibuya K

doi

10.1016/j.bmc.2016.05.048

subject

Has Abstract

pub_date

2016-08-15 00:00:00

pages

3436-46

issue

16

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(16)30379-0

journal_volume

24

pub_type

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