Trisubstituted 1,3,5-Triazines as Histamine H4 Receptor Antagonists with Promising Activity In Vivo

Author:

Olejarz-Maciej Agnieszka1ORCID,Mogilski Szczepan2ORCID,Karcz Tadeusz1ORCID,Werner Tobias3ORCID,Kamińska Katarzyna1,Kupczyk Jarosław1,Honkisz-Orzechowska Ewelina1ORCID,Latacz Gniewomir1ORCID,Stark Holger3ORCID,Kieć-Kononowicz Katarzyna1ORCID,Łażewska Dorota1ORCID

Affiliation:

1. Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9, 30-688 Kraków, Poland

2. Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9, 30-688 Kraków, Poland

3. Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany

Abstract

Pain is a very unpleasant experience that makes life extremely uncomfortable. The histamine H4 receptor (H4R) is a promising target for the treatment of inflammatory and immune diseases, as well as pain. H4R ligands have demonstrated analgesic effects in a variety of pain models, including inflammatory pain. Continuing the search for active H4R ligands among the alkyl derivatives of 1,3,5-triazine, we obtained 19 new compounds in two series: acyclic (I) and aliphatic (II). In vitro pharmacological evaluation showed their variable affinity for H4R. The majority of compounds showed a moderate affinity for this receptor (Ki > 100 nM), while all compounds tested in ß-arrestin and cAMP assays showed antagonistic activity. The most promising, compound 6, (4-(cyclopentylmethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine; Ki = 63 nM) was selected for further in vitro evaluation: blood-brain barrier permeability (PAMPA assay; Pe = 12.26 × 10−6 cm/s) and toxicity tests (HepG2 and SH-5YSY cells; no toxicity up to 50 µM). Next, compound 6 tested in vivo in a carrageenan-induced inflammatory pain model showed anti-inflammatory and analgesic effects (strongest at 50 mg/kg i.p.). Furthermore, in a histamine- and chloroquine-induced pruritus model, compound 6 at a dose of 25 mg/kg i.p. and 50 mg/kg i.p., respectively, reduced the number of scratch bouts. Thus, compound 6 is a promising ligand for further studies.

Funder

National Science Centre, Poland

Jagiellonian University Medical College in Kraków

DFG

Publisher

MDPI AG

Subject

Chemistry (miscellaneous),Analytical Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Molecular Medicine,Drug Discovery,Pharmaceutical Science

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