2,4-Diaminopyrimidines as histamine H4 receptor ligands—Scaffold optimization and pharmacological characterization

The human histamine H4 receptor (hH4R) is a promising new target in the therapy of inflammatory diseases and disorders of the immune system. For the development of new H4R antagonists a broad ligand-based virtual screening was performed resulting in two hits. The dissection of their common annelated aromatic core into its heteromonocyclic components showed that 2,4-diaminopyrimidine is a potent hH4R affinity scaffold, which was comprehensively investigated. Structure–activity relationship studies revealed that slight structural changes evoke extensive differences in functional activities and potencies: while o- and p-substituted benzyl amines mainly showed partial agonism, m-substituted and rigidified ones exhibited inverse agonist efficacy.

A combination of modern and classical approaches in bioinformatics and medicinal chemistry was applied to develop and investigate a 2,4-diaminopyrimidine scaffold as a pharmacophore of histamine H4 receptor ligands. Ligands were characterized regarding their affinity, efficacy and selectivity on the human histamine H4 receptor.Figure optionsDownload as PowerPoint slide