2,4-Diaminopyrimidines as histamine H4 receptor ligands--Scaffold optimization and pharmacological characterization.
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.
Sander
Kerstin
K
Johann Wolfgang Goethe-University, Institute of Pharmaceutical Chemistry, ZAFES/LiFF/CMP, Max-von-Laue-Str. 9, 60438 Frankfurt/Main, Germany.
Kottke
Tim
T
Tanrikulu
Yusuf
Y
Proschak
Ewgenij
E
Weizel
Lilia
L
Schneider
Erich H
EH
Seifert
Roland
R
Schneider
Gisbert
G
Stark
Holger
H
D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D011743:Pyrimidines / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011968:Receptors, Histamine / Q000378:metabolism*; D000074040:Receptors, Histamine H4; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
C418607:HRH4 protein, human; D008024:Ligands; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4