Ligand based design of novel histamine H₄ receptor antagonists; fragment optimization and analysis of binding kinetics

Bioorg Med Chem Lett. 2012 Jan 1;22(1):461-7. doi: 10.1016/j.bmcl.2011.10.104. Epub 2011 Nov 11.

Abstract

The histamine H(4) receptor is a G protein-coupled receptor that has attracted much interest for its role in inflammatory and immunomodulatory functions. In our search for new H(4)R ligands, a low affinity isoquinoline fragment was optimized to 7-(furan-2-yl)-4-(piperazin-1-yl)quinazolin-2-amine (VUF11489), as a new H(4)R antagonist. Analysis of its binding kinetics at the human H(4)R showed this compound to have a very different dissociative half-life in comparison with reference antagonist JNJ7777120.

MeSH terms

  • Animals
  • Biological Availability
  • Chemistry, Pharmaceutical / methods
  • Drug Design
  • Histamine Antagonists / chemical synthesis*
  • Histamine Antagonists / pharmacology
  • Humans
  • Hypersensitivity / drug therapy
  • Inhibitory Concentration 50
  • Kinetics
  • Ligands
  • Mice
  • Models, Chemical
  • Models, Molecular
  • Molecular Conformation
  • Rats
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / chemistry*
  • Receptors, Histamine / chemistry*
  • Receptors, Histamine H4
  • Structure-Activity Relationship
  • Time Factors

Substances

  • HRH4 protein, human
  • Histamine Antagonists
  • Ligands
  • Receptors, G-Protein-Coupled
  • Receptors, Histamine
  • Receptors, Histamine H4