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

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

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: mfkonono@cyf-kr.edu.pl.
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.

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