title: Bispyrimidines as potent histamine H(4) receptor ligands: delineation of structure-activity relationships and detailed H(4) receptor binding mode.
abstract: The basic methylpiperazine moiety is considered a necessary substructure for high histamine H4 receptor (H4R) affinity. This moiety is however also the metabolic hot spot for various classes of H4R ligands (e.g., indolcarboxamides and pyrimidines). We set out to investigate whether mildly basic 2-aminopyrimidines in combination with the appropriate linker can serve as a replacement for the methylpiperazine moiety. In the series of 2-aminopyrimidines, the introduction of an additional 2-aminopyrimidine moiety in combination with the appropriate linker lead to bispyrimidines displaying pKi values for binding the human H4R up to 8.2. Furthermore, the methylpiperazine replacement results in compounds with improved metabolic properties. The attempt to transfer the knowledge generated in the class of bispyrimidines to the indolecarboxamides failed. Combining the derived structure-activity relationships with homology modeling leads to new detailed insights in the molecular aspects of ligand-H4R binding in general and the binding mode of the described bispyrimidines in specific.
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG, Department of Medicinal Chemistry, Dr. Boehringergasse 5-11, 1121 Vienna, Austria.
authors.forename: Harald
authors.initials: H
authors.lastname: Engelhardt
authors.forename: Sabine
authors.initials: S
authors.lastname: Schultes
authors.forename: Chris
authors.initials: C
authors.lastname: de Graaf
authors.forename: Saskia
authors.initials: S
authors.lastname: Nijmeijer
authors.forename: Henry F
authors.initials: HF
authors.lastname: Vischer
authors.forename: Obbe P
authors.initials: OP
authors.lastname: Zuiderveld
authors.forename: Julia
authors.initials: J
authors.lastname: Dobler
authors.forename: Katharina
authors.initials: K
authors.lastname: Stachurski
authors.forename: Moriz
authors.initials: M
authors.lastname: Mayer
authors.forename: Heribert
authors.initials: H
authors.lastname: Arnhof
authors.forename: Dirk
authors.initials: D
authors.lastname: Scharn
authors.forename: Eric E J
authors.initials: EE
authors.lastname: Haaksma
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
mesh_terms: D000818:Animals; D001665:Binding Sites; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011789:Quantum Theory; D011869:Radioligand Assay; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism; D011968:Receptors, Histamine / Q000737:chemistry* / Q000378:metabolism; D000074040:Receptors, Histamine H4; D017386:Sequence Homology, Amino Acid; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: C418607:HRH4 protein, human; D008024:Ligands; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4