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

Bioorg Med Chem Lett. 2015 Mar 15;25(6):1274-8. doi: 10.1016/j.bmcl.2015.01.047. Epub 2015 Jan 28.

Abstract

In an attempt to molecularly design liver X receptor (LXR) β-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 LXRβ. We synthesized a series of 2-oxochromene derivatives and identified 43 as a LXRβ-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.

Keywords: 2-Oxochromene; Anti-atherosclerosis; HDL-C; LXRβ-selective; Liver X receptor.

MeSH terms

  • Animals
  • Aorta, Thoracic / drug effects
  • Aorta, Thoracic / metabolism
  • Benzopyrans / chemistry*
  • Benzopyrans / metabolism
  • Benzopyrans / pharmacology
  • Cholesterol, HDL / blood
  • Coumarins / chemistry*
  • Coumarins / metabolism
  • Coumarins / pharmacology
  • Cricetinae
  • Diet, High-Fat
  • Drug Design*
  • Hydantoins / chemistry*
  • Hydantoins / metabolism
  • Hydantoins / pharmacology
  • Imidazolines / chemistry
  • Liver X Receptors
  • Orphan Nuclear Receptors / agonists*
  • Orphan Nuclear Receptors / metabolism
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • 5-(4-methoxyphenyl)-5-methyl-3-(4-((2-oxo-8-n-propyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)butyl)imidazolidine-2,4-dione
  • Benzopyrans
  • Cholesterol, HDL
  • Coumarins
  • Hydantoins
  • Imidazolines
  • Liver X Receptors
  • Orphan Nuclear Receptors