Aryl-1,3,5-triazine derivatives as histamine H4 receptor ligands.

Abstract A series of novel 2-amino-4-(4-methylpiperazin-1-yl)-1,3,5-triazine derivatives with different aryl substituents in the 6-position was designed, synthesized and evaluated for histamine H 4 receptor (H 4 R) affinity in S f 9 cells expressing human H 4 R co-expressed with G-protein subunits. Triazine derivative 8 with a 6-( p -chlorophenyl) substituent showed the highest affinity with hH 4 R K i value of 203 nM and was classified as an antagonist in cAMP accumulation assay. This compound, identified as a new lead structure, demonstrated also anti-inflammatory properties in preliminary studies in mice (carrageenan-induced edema test) and neither possessed significant antiproliferative activity, nor modulated CYP3A4 activity up to concentration of 25 μM. In order to discuss structure–activity relationships molecular modeling and docking studies were undertaken.