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

  • Eur J Med Chem. 2014 Aug 18:83:534-46. doi: 10.1016/j.ejmech.2014.06.032.
Dorota Łażewska  1 ,  Małgorzata Więcek  1 ,  Joanna Ner  1 ,  Katarzyna Kamińska  1 ,  Tim Kottke  2 ,  J Stephan Schwed  2 ,  Małgorzata Zygmunt  3 ,  Tadeusz Karcz  1 ,  Agnieszka Olejarz  1 ,  Kamil Kuder  1 ,  Gniewomir Latacz  1 ,  Marek Grosicki  1 ,  Jacek Sapa  3 ,  Janina Karolak-Wojciechowska  4 ,  Holger Stark  5 ,  Katarzyna Kieć-Kononowicz  6
Affiliations
  • 1. Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Kraków, Poland.
  • 2. Goethe University, Institute of Pharmaceutical Chemistry, Biozentrum, ZAFES/CMP/ICNF, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
  • 3. Department of Pharmacodynamics, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Kraków, Poland.
  • 4. Institute of General and Ecological Chemistry, Technical University of Łódź, Żeromskiego 116 Str., 90-924 Łódź, Poland.
  • 5. Goethe University, Institute of Pharmaceutical Chemistry, Biozentrum, ZAFES/CMP/ICNF, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany; Heinrich-Heine-University, Institute of Pharmaceutical and Medicinal Chemistry, Universitaetsstr. 1, 40225 Duesseldorf, Germany.
  • 6. Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Kraków, Poland. Electronic address: [email protected].
PMID: 24996140 DOI: 10.1016/j.ejmech.2014.06.032
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 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.

Keywords
2,4,6-Trisubstituted 1,3,5-triazines; 4-Methylpiperazines; Anti-inflammatory properties; Histamine H(4) receptor.