title: Ligand based design of novel histamine H₄ receptor antagonists; fragment optimization and analysis of binding kinetics.
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.
authors.affiliation: Griffin Discoveries BV, Department of Medicinal Chemistry, Room P-246, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Rogier A
authors.initials: RA
authors.lastname: Smits
authors.forename: Herman D
authors.initials: HD
authors.lastname: Lim
authors.forename: Tiffany
authors.initials: T
authors.lastname: van der Meer
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Kuhne
authors.forename: Karin
authors.initials: K
authors.lastname: Bessembinder
authors.forename: Obbe P
authors.initials: OP
authors.lastname: Zuiderveld
authors.forename: Maikel
authors.initials: M
authors.lastname: Wijtmans
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; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008024:Ligands; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011968:Receptors, Histamine / Q000737:chemistry*; D000074040:Receptors, Histamine H4; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: C418607:HRH4 protein, human; D006633:Histamine Antagonists; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4