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Rob Leurs - One of the best experts on this subject based on the ideXlab platform.

  • structure based virtual screening for fragment like ligands of the g protein coupled Histamine H4 Receptor
    MedChemComm, 2015
    Co-Authors: Rogier A. Smits, Iwan J. P. De Esch, Saskia Nijmeijer, Albert J. Kooistra, Henry F. Vischer, Enade Perdana Istyastono, Martien Kuijer, Luc Roumen, Rob Leurs
    Abstract:

    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.

  • Mapping Histamine H4 Receptor–ligand binding modes
    MedChemComm, 2013
    Co-Authors: Sabine Schultes, Rob Leurs, Iwan J. P. De Esch, Saskia Nijmeijer, Harald Engelhardt, Albert J. Kooistra, Henry F. Vischer, Eric E. J. Haaksma, Chris De Graaf
    Abstract:

    The increasing number of G protein-coupled Receptor (GPCR) crystal structures offers new opportunities for Histamine Receptor homology modeling. However, computational prediction of ligand binding modes in GPCRs such as the Histamine H4 Receptor (H4R), a Receptor that plays an important role in inflammation, remains a challenging task. In the current work we have combined complementary in silico Receptor modeling approaches with in vitro ligand structure–activity relationship (SAR) and protein site-directed mutagenesis studies to elucidate the binding modes of different ligand classes in H4R. By systematically considering different H4R modelling templates, ligand binding poses, and ligand protonation states in combination with docking and MD simulations we are able to explain ligand-specific mutation effects and subtle differences in ligand SAR. Our studies confirm that a combined theoretical and experimental approach represents a powerful strategy to map ligand–protein interactions.

  • analysis of multiple Histamine H4 Receptor compound classes uncovers gαi protein and β arrestin2 biased ligands
    Molecular Pharmacology, 2012
    Co-Authors: Saskia Nijmeijer, Henry F. Vischer, Elizabeth M Rosethorne, Steven J Charlton, Rob Leurs
    Abstract:

    After the recent description of β-arrestin2 recruitment to the human Histamine H4 Receptor (hH4R) in response to the well known H4R antagonist 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methyl-piperazine (JNJ 7777120), we evaluated in this study the efficacy of 31 known hH4R ligands to induce Gαi protein signaling and β-arrestin2 recruitment by the hH4R. The selected hH4R ligands belong to nine different structural classes that partly cover (pre)clinical trial candidates. We have identified hH4R ligands with a significant bias for the Gαi protein or β-arrestin2 pathway on the basis of efficacy differences. In addition, hH4R antagonists that did not show positive efficacy in either functional readouts were found. A common trend in pathway preference for the nine different ligand classes could not be observed. In particular, the isothiourea class shows very diverse results, varying from Gαi protein-biased or β-arrestin2-biased to nonbiased antagonists upon minor structural changes. The identified biased hH4R ligands are important pharmacological tools to unravel the significance of biased hH4R signaling in H4R pharmacology.

  • Ligand based design of novel Histamine H4 Receptor antagonists; fragment optimization and analysis of binding kinetics,
    Bioorganic & medicinal chemistry letters, 2011
    Co-Authors: Rogier A. Smits, Herman D. Lim, Iwan J. P. De Esch, Tiffany Van Der Meer, Sebastiaan Kuhne, Karin Bessembinder, Obbe P. Zuiderveld, Maikel Wijtmans, Rob Leurs
    Abstract:

    Abstract The Histamine H4 Receptor is a G protein-coupled Receptor that has attracted much interest for its role in inflammatory and immunomodulatory functions. In our search for new H4R ligands, a low affinity isoquinoline fragment was optimized to 7-(furan-2-yl)-4-(piperazin-1-yl)quinazolin-2-amine (VUF11489), as a new H4R antagonist. Analysis of its binding kinetics at the human H4R showed this compound to have a very different dissociative half-life in comparison with reference antagonist JNJ7777120.

  • Synthesis and QSAR of quinazoline sulfonamides as highly potent human Histamine H4 Receptor inverse agonists.
    Journal of medicinal chemistry, 2010
    Co-Authors: Rogier A. Smits, Gabriella Coruzzi, Maristella Adami, Rob Leurs, Cindy M. E. Van Dam, Obbe P. Zuiderveld, Enade Perdana Istyastono, Frans J. J. De Kanter, Aldo Jongejan, Iwan J. P. De Esch
    Abstract:

    Hit optimization of the class of quinazoline containing Histamine H4 Receptor (H4R) ligands resulted in a sulfonamide substituted analogue with high affinity for the H4R. This moiety leads to improved physicochemical properties and is believed to probe a distinct H4R binding pocket that was previously identified using pharmacophore modeling. By introducing a variety of sulfonamide substituents, the H4R affinity was optimized. The interaction of the new ligands, in combination with a set of previously published quinazoline compounds, was described by a QSAR equation. Pharmacological studies revealed that the sulfonamide analogues have excellent H4R affinity and behave as inverse agonists at the human H4R. In vivo evaluation of the potent 2-(6-chloro-2-(4-methylpiperazin-1-yl)quinazoline-4-amino)-N-phenylethanesulfonamide (54) (pKi = 8.31 ± 0.10) revealed it to have anti-inflammatory activity in an animal model of acute inflammation.

Iwan J. P. De Esch - One of the best experts on this subject based on the ideXlab platform.

  • structure based virtual screening for fragment like ligands of the g protein coupled Histamine H4 Receptor
    MedChemComm, 2015
    Co-Authors: Rogier A. Smits, Iwan J. P. De Esch, Saskia Nijmeijer, Albert J. Kooistra, Henry F. Vischer, Enade Perdana Istyastono, Martien Kuijer, Luc Roumen, Rob Leurs
    Abstract:

    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.

  • Mapping Histamine H4 Receptor–ligand binding modes
    MedChemComm, 2013
    Co-Authors: Sabine Schultes, Rob Leurs, Iwan J. P. De Esch, Saskia Nijmeijer, Harald Engelhardt, Albert J. Kooistra, Henry F. Vischer, Eric E. J. Haaksma, Chris De Graaf
    Abstract:

    The increasing number of G protein-coupled Receptor (GPCR) crystal structures offers new opportunities for Histamine Receptor homology modeling. However, computational prediction of ligand binding modes in GPCRs such as the Histamine H4 Receptor (H4R), a Receptor that plays an important role in inflammation, remains a challenging task. In the current work we have combined complementary in silico Receptor modeling approaches with in vitro ligand structure–activity relationship (SAR) and protein site-directed mutagenesis studies to elucidate the binding modes of different ligand classes in H4R. By systematically considering different H4R modelling templates, ligand binding poses, and ligand protonation states in combination with docking and MD simulations we are able to explain ligand-specific mutation effects and subtle differences in ligand SAR. Our studies confirm that a combined theoretical and experimental approach represents a powerful strategy to map ligand–protein interactions.

  • Ligand based design of novel Histamine H4 Receptor antagonists; fragment optimization and analysis of binding kinetics,
    Bioorganic & medicinal chemistry letters, 2011
    Co-Authors: Rogier A. Smits, Herman D. Lim, Iwan J. P. De Esch, Tiffany Van Der Meer, Sebastiaan Kuhne, Karin Bessembinder, Obbe P. Zuiderveld, Maikel Wijtmans, Rob Leurs
    Abstract:

    Abstract The Histamine H4 Receptor is a G protein-coupled Receptor that has attracted much interest for its role in inflammatory and immunomodulatory functions. In our search for new H4R ligands, a low affinity isoquinoline fragment was optimized to 7-(furan-2-yl)-4-(piperazin-1-yl)quinazolin-2-amine (VUF11489), as a new H4R antagonist. Analysis of its binding kinetics at the human H4R showed this compound to have a very different dissociative half-life in comparison with reference antagonist JNJ7777120.

  • Synthesis and QSAR of quinazoline sulfonamides as highly potent human Histamine H4 Receptor inverse agonists.
    Journal of medicinal chemistry, 2010
    Co-Authors: Rogier A. Smits, Gabriella Coruzzi, Maristella Adami, Rob Leurs, Cindy M. E. Van Dam, Obbe P. Zuiderveld, Enade Perdana Istyastono, Frans J. J. De Kanter, Aldo Jongejan, Iwan J. P. De Esch
    Abstract:

    Hit optimization of the class of quinazoline containing Histamine H4 Receptor (H4R) ligands resulted in a sulfonamide substituted analogue with high affinity for the H4R. This moiety leads to improved physicochemical properties and is believed to probe a distinct H4R binding pocket that was previously identified using pharmacophore modeling. By introducing a variety of sulfonamide substituents, the H4R affinity was optimized. The interaction of the new ligands, in combination with a set of previously published quinazoline compounds, was described by a QSAR equation. Pharmacological studies revealed that the sulfonamide analogues have excellent H4R affinity and behave as inverse agonists at the human H4R. In vivo evaluation of the potent 2-(6-chloro-2-(4-methylpiperazin-1-yl)quinazoline-4-amino)-N-phenylethanesulfonamide (54) (pKi = 8.31 ± 0.10) revealed it to have anti-inflammatory activity in an animal model of acute inflammation.

  • Major advances in the development of Histamine H4 Receptor ligands.
    Drug discovery today, 2009
    Co-Authors: Rogier A. Smits, Rob Leurs, Iwan J. P. De Esch
    Abstract:

    The search for new and potent Histamine H4 Receptor ligands is leading to a steadily increasing number of scientific publications and patent applications. Several interesting and structurally diverse compounds have been found, but fierce IP competition for a preferred 2-aminopyrimidine scaffold is becoming apparent. Recent investigations into the role of the Histamine H(4)R in (patho)physiology and the use of H4R ligands in in vivo disease models reveal enormous potential in the field of inflammation and allergy, among others. The development of ligands that display activity at two or more Histamine Receptor (HR) subtypes is another clinical opportunity that is currently being explored. Taken together, the Histamine H4R field is gearing up for clinical studies and has the potential to deliver another generation of blockbuster drugs.

Rogier A. Smits - One of the best experts on this subject based on the ideXlab platform.

  • structure based virtual screening for fragment like ligands of the g protein coupled Histamine H4 Receptor
    MedChemComm, 2015
    Co-Authors: Rogier A. Smits, Iwan J. P. De Esch, Saskia Nijmeijer, Albert J. Kooistra, Henry F. Vischer, Enade Perdana Istyastono, Martien Kuijer, Luc Roumen, Rob Leurs
    Abstract:

    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.

  • Ligand based design of novel Histamine H4 Receptor antagonists; fragment optimization and analysis of binding kinetics,
    Bioorganic & medicinal chemistry letters, 2011
    Co-Authors: Rogier A. Smits, Herman D. Lim, Iwan J. P. De Esch, Tiffany Van Der Meer, Sebastiaan Kuhne, Karin Bessembinder, Obbe P. Zuiderveld, Maikel Wijtmans, Rob Leurs
    Abstract:

    Abstract The Histamine H4 Receptor is a G protein-coupled Receptor that has attracted much interest for its role in inflammatory and immunomodulatory functions. In our search for new H4R ligands, a low affinity isoquinoline fragment was optimized to 7-(furan-2-yl)-4-(piperazin-1-yl)quinazolin-2-amine (VUF11489), as a new H4R antagonist. Analysis of its binding kinetics at the human H4R showed this compound to have a very different dissociative half-life in comparison with reference antagonist JNJ7777120.

  • Synthesis and QSAR of quinazoline sulfonamides as highly potent human Histamine H4 Receptor inverse agonists.
    Journal of medicinal chemistry, 2010
    Co-Authors: Rogier A. Smits, Gabriella Coruzzi, Maristella Adami, Rob Leurs, Cindy M. E. Van Dam, Obbe P. Zuiderveld, Enade Perdana Istyastono, Frans J. J. De Kanter, Aldo Jongejan, Iwan J. P. De Esch
    Abstract:

    Hit optimization of the class of quinazoline containing Histamine H4 Receptor (H4R) ligands resulted in a sulfonamide substituted analogue with high affinity for the H4R. This moiety leads to improved physicochemical properties and is believed to probe a distinct H4R binding pocket that was previously identified using pharmacophore modeling. By introducing a variety of sulfonamide substituents, the H4R affinity was optimized. The interaction of the new ligands, in combination with a set of previously published quinazoline compounds, was described by a QSAR equation. Pharmacological studies revealed that the sulfonamide analogues have excellent H4R affinity and behave as inverse agonists at the human H4R. In vivo evaluation of the potent 2-(6-chloro-2-(4-methylpiperazin-1-yl)quinazoline-4-amino)-N-phenylethanesulfonamide (54) (pKi = 8.31 ± 0.10) revealed it to have anti-inflammatory activity in an animal model of acute inflammation.

  • Major advances in the development of Histamine H4 Receptor ligands.
    Drug discovery today, 2009
    Co-Authors: Rogier A. Smits, Rob Leurs, Iwan J. P. De Esch
    Abstract:

    The search for new and potent Histamine H4 Receptor ligands is leading to a steadily increasing number of scientific publications and patent applications. Several interesting and structurally diverse compounds have been found, but fierce IP competition for a preferred 2-aminopyrimidine scaffold is becoming apparent. Recent investigations into the role of the Histamine H(4)R in (patho)physiology and the use of H4R ligands in in vivo disease models reveal enormous potential in the field of inflammation and allergy, among others. The development of ligands that display activity at two or more Histamine Receptor (HR) subtypes is another clinical opportunity that is currently being explored. Taken together, the Histamine H4R field is gearing up for clinical studies and has the potential to deliver another generation of blockbuster drugs.

  • Pharmacological characterization of the new Histamine H4 Receptor agonist VUF 8430.
    British Journal of Pharmacology, 2009
    Co-Authors: Herman D. Lim, Ralf Gutzmer, Thomas Werfel, Gabriella Coruzzi, Maristella Adami, Elena Guaita, Rogier A. Smits, Iwan J. P. De Esch, Remko A. Bakker, Rob Leurs
    Abstract:

    Background and purpose:  We compare the pharmacological profiles of a new Histamine H4 Receptor agonist 2-(2-guanidinoethyl)isothiourea (VUF 8430) with that of a previously described H4 Receptor agonist, 4-methylHistamine. Experimental approach:  Radioligand binding and functional assays were performed using Histamine H4 Receptors expressed in mammalian cell lines. Compounds were also evaluated ex vivo in monocyte-derived dendritic cells endogenously expressing H4 Receptors and in vivo in anaesthetized rats for gastric acid secretion activity. Key results:  Both VUF 8430 and 4-methylHistamine were full agonists at human H4 Receptors with lower affinity at rat and mouse H4 Receptors. Both compounds induced chemotaxis of monocyte-derived dendritic cells. VUF 8430 also showed reasonable affinity and was a full agonist at the H3 Receptor. Agmatine is a metabolite of arginine, structurally related to VUF 8430, and was a H4 Receptor agonist with micromolar affinity. At Histamine H3 Receptors, agmatine was a full agonist, whereas 4-methylHistamine was an agonist only at high concentrations. Both VUF 8430 and agmatine were inactive at H1 and H2 Receptors, whereas 4-methylHistamine is as active as Histamine at H2 Receptors. In vivo, VUF 8430 only caused a weak secretion of gastric acid mediated by H2 Receptors, whereas 4-methylHistamine, dimaprit, Histamine and amthamine, at equimolar doses, induced 2.5- to 6-fold higher output than VUF 8430. Conclusions and implications:  Our results suggest complementary use of 4-methylHistamine and VUF 8430 as H4 Receptor agonists. Along with H4 Receptor antagonists, both agonists can serve as useful pharmacological tools in studies of Histamine H4 Receptors.

Robin L. Thurmond - One of the best experts on this subject based on the ideXlab platform.

  • Clinical Development of Histamine H4 Receptor Antagonists
    Handbook of experimental pharmacology, 2017
    Co-Authors: Robin L. Thurmond, Paul J. Dunford, Jennifer D. Venable, Brad M. Savall, Sandra Snook, James P. Edwards
    Abstract:

    The discovery of the Histamine H4 Receptor (H4R) provided a new avenue for the exploration of the physiological role of Histamine, as well as providing a new drug target for the development of novel antiHistamines. The first step in this process was the identification of selective antagonists to help unravel the pharmacology of the H4R relative to other Histamine Receptors. The discovery of the selective H4R antagonist JNJ 7777120 was vital for showing a role for the H4R in inflammation and pruritus. While this compound has been very successful as a tool for understanding the function of the Receptor, it has drawbacks, including a short in vivo half-life and hypoadrenocorticism toxicity in rats and dogs, that prevented advancing it into clinical studies. Further research let to the discovery of JNJ 39758979, which, similar to JNJ 7777120, was a potent and selective H4R antagonist and showed anti-inflammatory and anti-pruritic activity preclinically. JNJ 39758979 advanced into human clinical studies and showed efficacy in reducing experimental pruritus and in patients with atopic dermatitis. However, development of this compound was terminated due to the occurrence of drug-induced agranulocytosis. This was overcome by developing another H4R antagonist with a different chemical structure, toreforant, that does not appear to have this side effect. Toreforant has been tested in clinical studies in patients with rheumatoid arthritis, asthma, or psoriasis. In conclusions there have been many H4R antagonists reported in the literature, but only a few have been studied in humans underscoring the difficulty in finding ligands with all of the properties necessary for testing in the clinic. Nevertheless, the clinical data to date suggests that H4R antagonists can be beneficial in treating atopic dermatitis and pruritus.

  • The Role of Histamine H4 Receptor in Asthma and Atopic Dermatitis
    Histamine Receptors, 2016
    Co-Authors: Robin L. Thurmond
    Abstract:

    Histamine acts through four different Receptors and ligands for two of these Receptors have been used in clinical practice for many decades. Efficacy of drugs that target the Histamine H1 Receptor in allergic disease such as urticaria, allergic rhinitis and allergic conjunctivitis has provided a rationale for the association of Histamine with allergy. However, these drugs are not efficacious in other diseases thought to be allergic in nature such as asthma and atopic dermatitis. Recent preclinical and clinical data has shown a role for Histamine H4 Receptor antagonists in these diseases. Histamine H4 Receptor antagonists are efficacious in preclinical models of asthma, atopic dermatitis and pruritus. One Histamine H4 Receptor antagonists, JNJ 39758979, has shown clinical efficacy in reducing Histamine-induced pruritus and in improving the skin lesions and pruritus in patients with atopic dermatitis. Therefore, the Histamine H4 Receptor may play a role in diseases such as asthma and atopic dermatitis, which have long since been believed not to be mediated by Histamine due to lack of efficacy of traditional antiHistamines.

  • The Histamine H4 Receptor: from orphan to the clinic.
    Frontiers in pharmacology, 2015
    Co-Authors: Robin L. Thurmond
    Abstract:

    The Histamine H4 Receptor (H4R) was first noted as a sequence in genomic databases that had features of a class A G-protein coupled Receptor. This putative Receptor was found to bind Histamine consistent with its homology to other Histamine Receptors and thus became the fourth member of the Histamine Receptor family. Due to the previous success of drugs that target the H1 and H2 Receptors, an effort was made to understand the function of this new Receptor and determine if it represented a viable drug target. Taking advantage of the vast literature on the function of Histamine, a search for Histamine activity that did not appear to be mediated by the other three Histamine Receptors was undertaken. From this asthma and pruritus emerged as areas of particular interest. Histamine has long been suspected to play a role in the pathogenesis of asthma, but antiHistamines that target the H1 and H2 Receptors have not been shown to be effective for this condition. The use of selective ligands in animal models of asthma has now potentially filled this gap by showing a role for the H4R in mediating lung function and inflammation. A similar story exists for chronic pruritus associated with conditions such as atopic dermatitis. AntiHistamines that target the H1 Receptor are effective in reducing acute pruritus, but are ineffective in pruritus experienced by patients with atopic dermatitis. As for asthma, animal models have now suggested a role for the H4R in mediating pruritic responses, with antagonists of the H4R reducing pruritus in a number of different conditions. The anti-pruritic effect of H4R antagonists has recently been shown in human clinical studies, validating the preclinical findings in the animal models. A selective H4R antagonist inhibited Histamine-induced pruritus in health volunteers and reduced pruritus in patients with atopic dermatitis. The history to date of the H4R provides an excellent example of the deorphanization of a novel Receptor and the translation of this into clinical efficacy in humans.

  • Tricyclic aminopyrimidine Histamine H4 Receptor antagonists.
    Bioorganic & medicinal chemistry letters, 2011
    Co-Authors: Savall Brad M, Laurent Gomez, Frank Chavez, Michael P. Curtis, Meduna Steven P, Kearney Aaron M, Paul J. Dunford, Jeffery M. Cowden, Robin L. Thurmond, Cheryl A. Grice
    Abstract:

    This report discloses the development of a series of tricyclic Histamine H4 Receptor antagonists. Starting with a low nanomolar benzofuranopyrimidine HTS hit devoid of pharmaceutically acceptable properties, we navigated issues with metabolism and solubility to furnish a potent, stable and water soluble tricyclic Histamine H4 Receptor antagonist with desirable physiochemical parameters which demonstrated efficacy a mouse ova model.

  • Histamine H4 Receptor antagonism diminishes existing airway inflammation and dysfunction via modulation of Th2 cytokines
    Respiratory research, 2010
    Co-Authors: Jeffery M. Cowden, Robin L. Thurmond, Jing Ying, Jason P. Riley, Paul J. Dunford
    Abstract:

    Background: Airway remodeling and dysfunction are characteristic features of asthma thought to be caused by aberrant production of Th2 cytokines. Histamine H4 Receptor (H4R) perturbation has previously been shown to modify acute inflammation and Th2 cytokine production in a murine model of asthma. We examined the ability of H4R antagonists to therapeutically modify the effects of Th2 cytokine production such as goblet cell hyperplasia (GCH), and collagen deposition in a sub-chronic model of asthma. In addition, effects on Th2 mediated lung dysfunction were also determined. Methods: Mice were sensitized to ovalbumin (OVA) followed by repeated airway challenge with OVA. After inflammation was established mice were dosed with the H4R antagonist, JNJ 7777120, or anti-IL-13 antibody for comparison. Airway hyperreactivity (AHR) was measured, lungs lavaged and tissues collected for analysis.

György M. Keserü - One of the best experts on this subject based on the ideXlab platform.

  • Novel Histamine H4 Receptor ligands and their potential therapeutic applications: an update
    Expert opinion on therapeutic patents, 2014
    Co-Authors: Róbert Gábor Kiss, György M. Keserü
    Abstract:

    Introduction: Histamine H4 Receptor (H4R) has been shown to be involved in various inflammatory conditions. Ligands acting on H4R show therapeutic potential in various diseases. For the first time, the positive proof-of-concept clinical trials of the H4 antagonist JNJ39758979 have demonstrated this potential in Histamine-induced pruritus. Besides role of H4R in inflammatory conditions, preclinical results in cancer, neuropathic pain, vestibular disorders and type 2 diabetes show the diverse signaling network modulated by H4R. This suggests further potential for H4 ligands in such diseases.Areas covered: In this review, we have summarized patent applications and papers of the H4R field published between 2012 and 2014. Additionally, we have analyzed the quality of the already described H4 ligands in terms of their ligand efficiency, lipophilic ligand efficiency and lipophilicity-corrected ligand efficiency.Expert opinion: We demonstrate that the number of published patent applications reached a maximum in 2...

  • Histamine H4 Receptor ligands and their potential therapeutic applications
    Expert opinion on therapeutic patents, 2009
    Co-Authors: Robert Kiss, György M. Keserü
    Abstract:

    Background: The Histamine H4 Receptor (H4R) was first cloned in 2000. As a new member of the Histamine Receptor family it was of great interest and a promising drug target for the treatment of inflammatory diseases. Recent studies suggest that H4 antagonists have therapeutic potential, even in several pain conditions. Initially, pharmacological processes mediated by H4R were analyzed primarily by non-selective H4 ligands. Since then, some highly potent and selective H4 antagonists have been reported by different groups. Several companies are working on the development of potent H4 antagonists, although the number of published patent applications is still low. Objective: This review aims to give an overview of the ligands acting on H4R, this is drawn from published in papers and patent applications. Methods: Analysis of scaffolds possessing significant H4 activity and review of their therapeutic potential. Results/conclusion: The pharmacology of currently available selective H4 ligands suggests therapeutic...

  • Activation Mechanism of the Human Histamine H4 Receptor - An Explicit Membrane Molecular Dynamics Simulation Study
    Journal of chemical information and modeling, 2008
    Co-Authors: Balázs Jójárt, Robert Kiss, Béla Viskolcz, György M. Keserü
    Abstract:

    Molecular dynamics (MD) simulations in a membrane-embedded environment were carried out on the homology model of the human Histamine H4 Receptor (hH4R) alone and in complex with its endogenous activator Histamine and with the first reported selective hH4R antagonist JNJ7777120. During the simulation of the Histamine-hH4R complex, considerable changes occurred in the hH4R structure as well as in the interaction pattern of Histamine at the binding site. These changes are in agreement with experimental data published on GPCR activation. In particular, the intracellular side of TM helix VI moved significantly away from TM helices III and VII. Moreover, Histamine formed an interaction with Asn147 (4.57) that was previously proved to be important in hH4R activation. Results of the MD simulations of the native hH4R and the JNJ7777120-hH4R complex suggest that these models represent an inactive conformation of hH4R. MD simulation in the presence of JNJ7777120 resulted in the movement of the intracellular side of ...

  • Discovery of novel human Histamine H4 Receptor ligands by large-scale structure-based virtual screening.
    Journal of medicinal chemistry, 2008
    Co-Authors: Robert Kiss, Bela Kiss, Árpád Könczöl, Ferenc Szalai, Ivett Jelinek, Valéria László, Béla Noszál, András Falus, György M. Keserü
    Abstract:

    A structure-based virtual screening (SBVS) was conducted on a ligand-supported homology model of the human Histamine H4 Receptor (hH4R). More than 8.7 million 3D structures derived from different vendor databases were investigated by docking to the hH4R binding site using FlexX. A total of 255 selected compounds were tested by radioligand binding assay and 16 of them possessed significant [3H]Histamine displacement. Several novel scaffolds were identified that can be used to develop selective H4 ligands in the future. As far as we know, this is the first SBVS reported on H4R, representing one of the largest virtual screens validated by the biological evaluation of the virtual hits.

  • Binding mode analysis and enrichment studies on homology models of the human Histamine H4 Receptor
    European journal of medicinal chemistry, 2007
    Co-Authors: Robert Kiss, Béla Noszál, András Falus, Ákos Rácz, Dániel Eros, György M. Keserü
    Abstract:

    Ligand-supported homology models of the human Histamine H4 Receptor (hH4R) were developed based on the crystal structure of bovine rhodopsin and different known H4 ligands (Histamine, OUP-16, JNJ7777120). Enrichment tests were performed to analyze whether our hH4R models can select known actives from random decoys. The impact of Receptor conformation and the effect of different sets of random decoys, docking methods (FlexX, FlexX-Pharm) and scoring functions (FlexX-Score, D-Score, PMF-Score, G-Score, ChemScore) were investigated. We found that two agonists (Histamine and OUP-16) form complementary interactions with Asp94 (3.32), Glu182 (5.46) and Thr323 (6.55), whereas JNJ7777120 interacts with Asp94 (3.32) and Glu182 (5.46) only. These results suggest a role of Thr323 (6.55) in ligand binding and presumably also in Receptor activation. The models optimized in the presence of an agonist (Histamine) and an antagonist (JNJ7777120) were compared in more detail. We conclude that the ligand used in the model building process can significantly influence the efficacy of virtual screening.