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Bioorg Med Chem. 2009 Oct 15;17(20):7186-96. doi: 10.1016/j.bmc.2009.08.059. Epub 2009 Sep 2.

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

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Johann Wolfgang Goethe-University, Institute of Pharmaceutical Chemistry, ZAFES/LiFF/CMP, Max-von-Laue-Str. 9, 60438 Frankfurt/Main, Germany.


The human histamine H(4) receptor (hH(4)R) is a promising new target in the therapy of inflammatory diseases and disorders of the immune system. For the development of new H(4)R 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 hH(4)R 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.

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