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

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 H4R ligands, a low affinity isoquinoline fragment was optimized to 7-(furan-2-yl)-4-(piperazin-1-yl)quinazolin-2-amine (VUF11489), as a new H4R antagonist. Analysis of its binding kinetics at the human H4R showed this compound to have a very different dissociative half-life in comparison with reference antagonist JNJ7777120. (C) 2011 Elsevier Ltd. All rights reserved.