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

• A series of 2,4,6-trisubstituted 1,3,5-triazines were obtained as potential histamine H4R ligands.
• Some compounds showed Ki values in the low submicromolar range.
• Some compounds exhibited in vivo anti-inflammatory activity.

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 H4 receptor (H4R) affinity in Sf9 cells expressing human H4R co-expressed with G-protein subunits. Triazine derivative 8 with a 6-(p-chlorophenyl) substituent showed the highest affinity with hH4R Ki 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.

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