Synthesis, in vitro and in vivo biological evaluation of new oxysterols as modulators of the liver X receptors

J Steroid Biochem Mol Biol. 2017 Jan;165(Pt B):323-330. doi: 10.1016/j.jsbmb.2016.07.010. Epub 2016 Jul 26.

Abstract

Liver X Receptor (LXR) modulators have shown potential as drugs since they target genes affecting metabolism and fatty acid synthesis. LXR antagonists are of particular interest since they are able to reduce the synthesis of complex fatty acids and glucose uptake. Based on molecular modeling, five new cholesterol mimics were synthesized, where four contained a hydroxyl group in the 22-S-position. The new compounds were screened in vitro against several genes affecting lipid metabolism. The compound that performed best in vitro was a dimethylamide derivative of 22(S)-hydroxycholesterol and it was chosen for in vivo testing. However, the blood plasma analysis from the in vivo tests revealed a concentration lower than needed to give any response, indicating either rapid metabolism or low bioavailability.

Keywords: Biological evaluation; Molecular modelling; Nuclear receptor modulation; Steroid synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1 / metabolism
  • Amides / chemistry
  • Animals
  • Cholesterol / chemistry
  • Drug Design
  • Fatty Acid Synthase, Type I / metabolism
  • Gene Expression
  • Glucose / chemistry
  • Hep G2 Cells
  • Humans
  • Lipogenesis
  • Liver X Receptors / antagonists & inhibitors*
  • Male
  • Molecular Docking Simulation
  • Oxysterols / chemistry*
  • Protein Binding
  • Rats
  • Rats, Wistar
  • Stearoyl-CoA Desaturase / metabolism
  • Triglycerides / chemistry
  • Weight Gain

Substances

  • ABCA1 protein, human
  • ATP Binding Cassette Transporter 1
  • Amides
  • Liver X Receptors
  • NR1H3 protein, human
  • Oxysterols
  • Triglycerides
  • Cholesterol
  • SCD1 protein, human
  • Stearoyl-CoA Desaturase
  • FASN protein, human
  • Fatty Acid Synthase, Type I
  • Glucose