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

Dorota Łażewska; Małgorzata Więcek; Joanna Ner; Katarzyna Kamińska; Tim Kottke; J Stephan Schwed; Małgorzata Zygmunt; Tadeusz Karcz; Agnieszka Olejarz; Kamil Kuder; Gniewomir Latacz; Marek Grosicki; Jacek Sapa; Janina Karolak-Wojciechowska; Holger Stark; Katarzyna Kieć-Kononowicz

doi:10.1016/j.ejmech.2014.06.032

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. Epub 2014 Jun 17.

Authors

Dorota Łażewska¹, Małgorzata Więcek¹, Joanna Ner¹, Katarzyna Kamińska¹, Tim Kottke², J Stephan Schwed², Małgorzata Zygmunt³, Tadeusz Karcz¹, Agnieszka Olejarz¹, Kamil Kuder¹, Gniewomir Latacz¹, Marek Grosicki¹, Jacek Sapa³, Janina Karolak-Wojciechowska⁴, Holger Stark⁵, Katarzyna Kieć-Kononowicz⁶

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / metabolism*
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Stability
Edema / drug therapy
Humans
Male
Mice
Molecular Docking Simulation
Protein Conformation
Receptors, G-Protein-Coupled / chemistry
Receptors, G-Protein-Coupled / metabolism*
Receptors, Histamine / chemistry
Receptors, Histamine / metabolism*
Receptors, Histamine H3 / metabolism
Receptors, Histamine H4
Substrate Specificity
Triazines / chemistry
Triazines / metabolism*
Triazines / pharmacology*
Triazines / therapeutic use

Substances

Anti-Inflammatory Agents, Non-Steroidal
HRH4 protein, human
Receptors, G-Protein-Coupled
Receptors, Histamine
Receptors, Histamine H3
Receptors, Histamine H4
Triazines