1028327-73-2Relevant academic research and scientific papers
Mapping histamine H4 receptor-ligand binding modes
Schultes, Sabine,Nijmeijer, Saskia,Engelhardt, Harald,Kooistra, Albert J.,Vischer, Henry F.,De Esch, Iwan J. P.,Haaksma, Eric E. J.,Leurs, Rob,De Graaf, Chris
, p. 193 - 204 (2013)
The increasing number of G protein-coupled receptor (GPCR) crystal structures offers new opportunities for histamine receptor homology modeling. However, computational prediction of ligand binding modes in GPCRs such as the histamine H4 receptor (H4R), a receptor that plays an important role in inflammation, remains a challenging task. In the current work we have combined complementary in silico receptor modeling approaches with in vitro ligand structure-activity relationship (SAR) and protein site-directed mutagenesis studies to elucidate the binding modes of different ligand classes in H4R. By systematically considering different H4R modelling templates, ligand binding poses, and ligand protonation states in combination with docking and MD simulations we are able to explain ligand-specific mutation effects and subtle differences in ligand SAR. Our studies confirm that a combined theoretical and experimental approach represents a powerful strategy to map ligand-protein interactions. The Royal Society of Chemistry 2013.
Structure-activity studies on a series of a 2-aminopyrimidine-containing histamine H4 receptor ligands
Altenbach, Robert J.,Adair, Ronald M.,Bettencourt, Brian M.,Black, Lawrence A.,Fix-Stenzel, Shannon R.,Gopalakrishnan, Sujatha M.,Hsieh, Gin C.,Liu, Huaqing,Marsh, Kennan C.,McPherson, Michael J.,Milicic, Ivan,Miller, Thomas R.,Vortherms, Timothy A.,Warrior, Usha,Wetter, Jill M.,Wishart, Neil,Witte, David G.,Honore, Prisca,Esbenshade, Timothy A.,Hancock, Arthur A.,Brioni, Jorge D.,Cowart, Marlon D.
supporting information; experimental part, p. 6571 - 6580 (2009/11/30)
A series of 2-aminopyrimidines was synthesized as ligands of the histamine H4 receptor (H4R). Working in part from a pyrimidine hit that was identified in an HTS campaign, SAR studies were carried out to optimize the potency, which led to compound 3,4-tert-butyl-6-(4-methylpiperazin-1-yl) pyrimidin-2-ylamine. We further studied this compound by systematically modifying the core pyrimidine moiety, the methylpiperazine at position 4, the NH2 at position 2, and positions 5 and 6 of the pyrimidine ring. The pyrimidine 6 position benefited the most from this optimization, especially in analogs in which the 6-tert-butyl was replaced with aromatic and secondary amine moieties. The highlight of the optimization campaign was compound 4,4-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]benzonitrile, which was potent in vitro and was active as an anti-inflammatory agent in an animal model and had antinociceptive activity in a pain model, which supports the potential of H4R antagonists in pain.
