title: 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 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.
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Kraków, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Łażewska
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Kraków, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Więcek
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Kraków, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Ner
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Kraków, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kamińska
authors.affiliation: Goethe University, Institute of Pharmaceutical Chemistry, Biozentrum, ZAFES/CMP/ICNF, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Kottke
authors.affiliation: Goethe University, Institute of Pharmaceutical Chemistry, Biozentrum, ZAFES/CMP/ICNF, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
authors.forename: J Stephan
authors.initials: JS
authors.lastname: Schwed
authors.affiliation: Department of Pharmacodynamics, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Kraków, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Zygmunt
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Kraków, Poland.
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Karcz
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Kraków, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Olejarz
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Kraków, Poland.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuder
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Kraków, Poland.
authors.forename: Gniewomir
authors.initials: G
authors.lastname: Latacz
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Kraków, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Grosicki
authors.affiliation: Department of Pharmacodynamics, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Kraków, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Sapa
authors.affiliation: Institute of General and Ecological Chemistry, Technical University of Łódź, Żeromskiego 116 Str., 90-924 Łódź, Poland.
authors.forename: Janina
authors.initials: J
authors.lastname: Karolak-Wojciechowska
authors.affiliation: 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.
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
authors.affiliation: 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.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kieć-Kononowicz
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004355:Drug Stability; D004487:Edema / Q000188:drug therapy; D006801:Humans; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism*; D011968:Receptors, Histamine / Q000737:chemistry / Q000378:metabolism*; D018100:Receptors, Histamine H3 / Q000378:metabolism; D000074040:Receptors, Histamine H4; D013379:Substrate Specificity; D014227:Triazines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C418607:HRH4 protein, human; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D000074040:Receptors, Histamine H4; D014227:Triazines
keywords: 2,4,6-Trisubstituted 1,3,5-triazines; 4-Methylpiperazines; Anti-inflammatory properties; Histamine H(4) receptor