Lead identification and optimization of diaminopyrimidines as histamine H4 receptor ligands.
BACKGROUND
The human histamine H(4) receptor (hH(4)R) is a promising new target in the therapy of inflammatory or immune system diseases.


METHODS
For the development of new hH(4)R ligands, a broad virtual screening was performed and two hits were identified. Their annelated heterocyclic core was optimized with regard to affinity and potency.


RESULTS
Pharmacological characterization of the resulting diaminopyrimidines revealed different agonist and antagonist properties within the same scaffold.
Sander
K
K
Institute of Pharmaceutical Chemistry, ZAFES/LiFF/CMP/OSF, Johann Wolfgang Goethe University, Frankfurt, Germany.
Kottke
T
T
Proschak
E
E
Tanrikulu
Y
Y
Schneider
E H
EH
Seifert
R
R
Schneider
G
G
Stark
H
H
D002460:Cell Line; D003198:Computer Simulation; D016208:Databases, Factual; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D019204:GTP-Binding Proteins / Q000737:chemistry; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000187:drug effects*; D011968:Receptors, Histamine / Q000737:chemistry / Q000187:drug effects*; D000074040:Receptors, Histamine H4; D013329:Structure-Activity Relationship
C418607:HRH4 protein, human; D006633:Histamine Antagonists; D008024:Ligands; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D019204:GTP-Binding Proteins