Quinoline-3-carboxamide containing sulfones as liver X receptor (LXR) agonists with binding selectivity for LXRbeta and low blood-brain penetration

Bioorg Med Chem Lett. 2010 Jan 15;20(2):689-93. doi: 10.1016/j.bmcl.2009.11.062. Epub 2009 Dec 3.

Abstract

A series of quinoline-3-carboxamide containing sulfones was prepared and found to have good binding affinity for LXRbeta and moderate binding selectivity over LXRalpha. The 8-Cl quinoline analog 33 with a high TPSA score, displayed 34-fold binding selectivity for LXRbeta over LXRalpha (LXRbeta IC(50)=16nM), good activity for inducing ABCA1 gene expression in a THP macrophage cell line, desired weak potency in the LXRalpha Gal4 functional assay, and low blood-brain barrier penetration in rat.

MeSH terms

  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Binding Sites
  • Blood-Brain Barrier / metabolism*
  • Cell Line
  • Computer Simulation
  • Humans
  • Hydrogen Bonding
  • Liver X Receptors
  • Orphan Nuclear Receptors / agonists*
  • Orphan Nuclear Receptors / metabolism
  • Protein Binding
  • Quinolines / chemical synthesis
  • Quinolines / chemistry*
  • Quinolines / pharmacokinetics
  • Rats
  • Structure-Activity Relationship
  • Sulfones / chemical synthesis
  • Sulfones / chemistry*
  • Sulfones / pharmacokinetics

Substances

  • ABCA1 protein, human
  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters
  • Liver X Receptors
  • NR1H3 protein, human
  • Nr1h3 protein, rat
  • Orphan Nuclear Receptors
  • Quinolines
  • Sulfones