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Amsterdam-Zuidoost, Netherlands

Coruzzi G.,University of Parma | Pozzoli C.,University of Parma | Adami M.,University of Parma | Grandi D.,University of Parma | And 4 more authors.
Experimental Dermatology

The effects of the histamine H 4 receptor antagonist JNJ7777120 were evaluated in a model of acute skin inflammation induced by local application of croton oil. The influence of strain on the effect of JNJ7777120 was investigated in four different mouse strains (CD-1, NMRI, BALB/c and C57BL/6J). In CD-1 mice, JNJ777720 (30-100mg/kg subcutaneously, s.c.) exerted a dose-dependent inhibition of croton oil-induced ear inflammation and polymorphonuclear leucocyte infiltration, as confirmed by histological evaluation of ear tissues. JNJ7777120 (30-100mg/kg) did not reduce ear oedema in NMRI, BALB/c or C57BL/6J mice. The positive control, dexamethasone (2mg/kg s.c.) induced significant anti-inflammatory effects only in CD-1 and NMRI mice. In these strains, also the histamine H 1-receptor blocker pyrilamine (30mg/kg s.c.) significantly reduced ear oedema at 2h after croton oil challenge, being as effective as JNJ7777120 in CD-1 mice. Taken together, these data demonstrate that the H 4 receptor antagonist JNJ7777120 may reduce acute croton oil-induced skin inflammation as effectively as H 1 receptor blockade. However, present experiments evidenced for the first time marked strain-related differences in the JNJ7777120 pharmacological activity, which have to be carefully considered when using this ligand to characterize histamine H 4 receptor functions in murine models and translating preclinical data to clinical human settings. © 2011 John Wiley & Sons A/S. Source

Andaloussi M.,Griffin Discoveries BV | Lim H.D.,Griffin Discoveries BV | Van Der Meer T.,Griffin Discoveries BV | Sijm M.,Griffin Discoveries BV | And 6 more authors.
Bioorganic and Medicinal Chemistry Letters

In this work we describe the optimization of a lead compound based on the quinazoline template to give a new series of potent pyrido[3,2-d]pyrimidines as histamine H4 receptor antagonists. The pyrido[3,2-d]pyrimidine ligands have significantly reduced hERG binding compared to clinical stage compound PF-3893787 while showing good affinities at the human and rodent histamine receptors. The receptor residence time of several of these new compounds was determined for the human H4R and compared with JNJ7777120 and PF-3893787. The pyrido[3,2-d]pyrimidines showed residence times lower than JNJ7777120 but comparable to the residence time of PF-3893787. Overall, the pyrido[3,2-d]pyrimidines show an excellent in vitro profile that warrants their further investigation in relevant models of human disease. © 2013 Elsevier Ltd. All rights reserved. Source

Engelhardt H.,Boehringer Ingelheim | Engelhardt H.,VU University Amsterdam | De Esch I.J.P.,VU University Amsterdam | Kuhn D.,Boehringer Ingelheim | And 11 more authors.
European Journal of Medicinal Chemistry

A series of 76 derivatives of the indolecarboxamide 1 were synthesized, which allows a detailed SAR investigation of this well known scaffold. The data enable the definition of a predictive QSAR model which identifies several compounds with an activity comparable to 1. A selection of these new H 4R antagonists was synthesized and a comparison of predicted and measured values demonstrates the robustness of the model (47-55). In addition to the H4-receptor activity general CMC and DMPK properties were investigated. Some of the new analogs are not only excellently soluble, but display a significantly increased half-life in mouse liver microsomes as well. These properties qualify these compounds as a possible new standard for future in vivo studies (e.g 51, 52 and 55). Moreover, the current studies also provide valuable information on the potential receptor ligand interactions between the indolcarboxamides and the H4R protein. © 2012 Elsevier Masson SAS. All rights reserved. Source

Kool J.,VU University Amsterdam | Rudebeck A.F.,VU University Amsterdam | Fleurbaaij F.,VU University Amsterdam | Nijmeijer S.,VU University Amsterdam | And 5 more authors.
Journal of Chromatography A

In the past years we developed high-resolution screening platforms involving separation of bioactive mixtures and on-line or at-line bioassays for a wide variety of biological targets with parallel mass spectrometric detection and identification. In the current research, we make a major step forward in the development of at-line bioassays by implementation of radioligand receptor binding and functional cellular assays to evaluate bioactvity and selectivity. We demonstrate a new platform for high-resolution metabolic profiling of lead compounds for functional activity and selectivity toward the human histamine H4 receptor (hH4R), a member of the large family of membrane-bound G protein-coupled receptors. In this platform analytical chemistry, cell biology and pharmacology are merged. The methodology is based on chromatographic separation of metabolic mixtures by HPLC coupled to high-resolution fractionation onto (multiple) microtiter well plates for complementary assaying. The methodology was used for efficient and rapid metabolic profiling of the drug clozapine and three selective hH4R lead compounds. With this new platform metabolites with undesired alterations in target selectivity profiles can be readily identified. Moreover, the parallel identification of metabolite structures, with accurate-mass measurements and MS/MS, allowed identification of liable metabolic 'hotspots' for further lead optimization and plays a central role in the workflow and in this study. The methodology can be easily adapted for use with other receptor screening formats. The efficient combination of pharmacological assays with analytical techniques by leveraging high-resolution at-line fractionation as a linking technology will allow implementation of comprehensive metabolic profiling in an early phase of the drug discovery process. © 2012 Elsevier B.V. Source

Istyastono E.P.,VU University Amsterdam | Istyastono E.P.,Sanata Dharma University | Kooistra A.J.,VU University Amsterdam | Vischer H.F.,VU University Amsterdam | And 7 more authors.

We have explored the possibilities and challenges of structure-based virtual screening (SBVS) against the human histamine H4 receptor (H4R), a key player in inflammatory responses. Several SBVS strategies, employing different H4R ligand conformations, were validated and optimized with respect to their ability to discriminate small fragment-like H4R ligands from true inactive fragments, and compared to ligand-based virtual screening (LBVS) approaches. SBVS studies with a molecular interaction fingerprint (IFP) scoring method enabled the identification of H4R ligands that were not identified in LBVS runs, demonstrating the scaffold hopping potential of combining molecular docking and IFP scoring. Retrospective VS evaluations against H4R homology models based on the histamine H1 receptor (H1R) crystal structure did not give higher enrichments of H4R ligands than H4R models based on the beta-2 adrenergic receptor (β2R). Complementary prospective SBVS studies against β2R-based and H1R-based H4R homology models led to the discovery of different new fragment-like H4R ligand chemotypes. Of the 37 tested compounds, 9 fragments (representing 5 different scaffolds) had affinities between 0.14 and 6.3 μM at the H4R. © The Royal Society of Chemistry. Source

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