JNJ-7777120

IC50: A Histamine H4 receptor antagonist with IC50 of 4.5 nM.

Histamine has been reported to play an important role in a large number of physiological processes. JNJ-7777120, the first potent and selective non-imidazole histamine H4 receptor antagonist with Ki of 4.5 nM, exhibits more than 1000-fold selectivity over the other histamine receptors. [1]

In vitro: It was reported that NJ 7777120 bound to the H4 receptor with a remarkably high affinity. It also demonstrated a greater selectivity over other histamine receptor antagonists. Moreover, JNJ 7777120 selectively targeted to potent H4 rather than 50 other molecular targets. [2]

In vivo: JNJ 7777120 showed an oral bioavailability of about 30% in rats and 100% in dogs, with a half-life of around 3 h in both rats and dogs. It was reported to inhibit histamine-induced chemotaxis and calcium influx in mouse bone marrow-derived mast cells. In addition, in mice, JNJ 7777120 could suppress the histamine-induced migration of tracheal mast cells from the connective tissue to the epithelium. Moreover, JNJ 7777120 was demonstrated to notably inhibit neutrophil infiltration in a mouse zymosan-induced peritonitis model. [2]

Clinical trial: So far, no clinical trial has been conducted.

References:
[1]Jablonowski JA, Grice CA, Chai W, Dvorak CA, Venable JD, Kwok AK, Ly KS, Wei J, Baker SM, Desai PJ, Jiang W, Wilson SJ, Thurmond RL, Karlsson L, Edwards JP, Lovenberg TW and Carruthers NI.  The first potent and selective non-imidazole human histamine H4 receptor antagonists. J Med Chem. 2003 Sep; 46(19): 3957-60.
[2]Thurmond RL, Desai PJ, Dunford PJ, Fung-Leung WP, Hofstra CL, Jiang W, Nguyen S, Riley JP, Sun S, Williams KN, Edwards JP and Karlsson L.  A potent and selective histamine H4 receptor antagonist with anti-inflammatory properties. J Pharmacol Exp Ther. 2004 Apr; 309(1): 404-13.

Opposite effects of mepyramine on JNJ 7777120-induced amelioration of experimentally induced asthma in mice in sensitization and provocation.[Pubmed:22272324]

PLoS One. 2012;7(1):e30285.

BACKGROUND: Histamine is detected in high concentrations in the airways during an allergic asthma response. In a murine model of allergic asthma, JNJ 7777120, an antagonist at the histamine H(4) receptor, reduces asthmatic symptoms, while the histamine H(1) receptor-selective antagonist mepyramine is virtually without effect. In the present study, we analyzed the effect of combined antagonism at the histamine H(1) and H(4) receptors in a murine asthma model in relation to the timing of their application, i.e. sensitization or provocation. METHODOLOGY/PRINCIPAL FINDINGS: Asthma was induced in mice by sensitization and provocation with ovalbumin. JNJ 7777120 and/or mepyramine were injected subcutaneously either during sensitization or during provocation, and typical asthma parameters were analyzed. JNJ 7777120, but not mepyramine, reduced serum concentrations of anti-OVA IgE, inflammatory infiltrations in lung tissue, and eosinophilia in bronchoalveolar-lavage (BAL)-fluids independently of the timing of application. Upon application of JNJ 7777120 plus mepyramine in combination during provocation, mepyramine inhibited the effects of JNJ 7777120. In contrast, when applied during sensitization, mepyramine enhanced the disease-ameliorating effects of JNJ 7777120. CONCLUSIONS/SIGNIFICANCE: Our study indicates that both histamine H(1) and H(4) receptors play important roles in the course of murine experimental asthma. Unexpectedly, the contribution of these receptors to the pathogenesis differs between the two phases, sensitization or provocation. Since in human asthma, repeated contact to the allergen is not only provocation but also a boost of sensitization, a combined pharmacological targeting of histamine H(1) and H(4) receptors could be taken into consideration as an option for the prevention of asthma and maybe other allergic diseases.

Detailed analysis of biased histamine H(4) receptor signalling by JNJ 7777120 analogues.[Pubmed:23351115]

Br J Pharmacol. 2013 Sep;170(1):78-88.

BACKGROUND AND PURPOSE: The histamine H(4) receptor, originally thought to signal merely through Galphai proteins, has recently been shown to also recruit and signal via beta-arrestin2. Following the discovery that the reference antagonist indolecarboxamide JNJ 7777120 appears to be a partial agonist in beta-arrestin2 recruitment, we have identified additional biased hH(4)R ligands that preferentially couple to Galphai or beta-arrestin2 proteins. In this study, we explored ligand and receptor regions that are important for biased hH(4)R signalling. EXPERIMENTAL APPROACH: We evaluated a series of 48 indolecarboxamides with subtle structural differences for their ability to induce hH(4)R-mediated Galphai protein signalling or beta-arrestin2 recruitment. Subsequently, a Fingerprints for Ligands and Proteins three-dimensional quantitative structure-activity relationship analysis correlated intrinsic activity values with structural ligand requirements. Moreover, a hH(4)R homology model was used to identify receptor regions important for biased hH(4)R signalling. KEY RESULTS: One indolecarboxamide (75) with a nitro substituent on position R7 of the aromatic ring displayed an equal preference for the Galphai and beta-arrestin2 pathway and was classified as unbiased hH(4)R ligand. The other 47 indolecarboxamides were beta-arrestin2-biased agonists. Intrinsic activities of the unbiased as well as beta-arrestin2-biased indolecarboxamides to induce beta-arrestin2 recruitment could be correlated with different ligand features and hH(4)R regions. CONCLUSION AND IMPLICATIONS: Small structural modifications resulted in diverse intrinsic activities for unbiased (75) and beta-arrestin2-biased indolecarboxamides. Analysis of ligand and receptor features revealed efficacy hotspots responsible for biased-beta-arrestin2 recruitment. This knowledge is useful for the design of hH(4)R ligands with biased intrinsic activities and aids our understanding of the mechanism of H(4)R activation.

The dual H3/4R antagonist thioperamide does not fully mimic the effects of the 'standard' H4R antagonist JNJ 7777120 in experimental murine asthma.[Pubmed:23820873]

Naunyn Schmiedebergs Arch Pharmacol. 2013 Nov;386(11):983-90.

Histamine is detected in high concentrations in the airways during an allergic asthma response. In a murine model of allergic asthma, the histamine H4 receptor (H4R)-selective ligand JNJ 7777120 reduces asthma-like symptoms. A sole antagonistic function of JNJ 7777120 at the murine H4R has, however, been questioned in the literature. Therefore, in the present study, we aimed at analyzing the effects of JNJ 7777120 in comparison to that of the H3/4R-selective antagonist thioperamide. Experimental murine asthma was induced by sensitization and provocation of BALB/c mice with ovalbumine (OVA). JNJ 7777120, thioperamide, or JNJ 5207852, an H3R-selective antagonist which was used to dissect H3R- and H4R-mediated activities of thioperamide, were injected subcutaneously during sensitization and effects were analyzed after provocation. Pharmacokinetic analyses revealed shortest t1/2 values in both plasma and lung tissue and lowest maximal concentration in lung tissue for JNJ 7777120 in comparison to thioperamide and JNJ 5207852. Nevertheless, JNJ 7777120 reduced serum titers of allergen-specific (anti-OVA) IgE, inflammatory infiltrations in lung tissue, and eosinophilia in bronchoalveolar lavage fluid. In contrast, thioperamide reduced only eosinophilia in bronchoalveolar lavage fluid, while anti-OVA IgE concentrations and lung infiltrations remained unaffected. JNJ 5207852 had no effect on these parameters. JNJ 7777120 provides beneficial effects in experimental murine asthma, which, however, could only partially be mimicked by thioperamide, despite more favorable pharmacokinetics. Thus, whether these effects of JNJ 7777120 are entirely attributable to an antagonistic activity at the murine H4R or whether an agonistic activity is also involved has to be reconsidered.

In vitro and in vivo characterization of A-940894: a potent histamine H4 receptor antagonist with anti-inflammatory properties.[Pubmed:19413570]

Br J Pharmacol. 2009 May;157(1):44-54.

BACKGROUND AND PURPOSE: The histamine H4 receptor is widely expressed in cells of immune origin and has been shown to play a role in a variety of inflammatory processes mediated by histamine. In this report, we describe the in vitro and in vivo anti-inflammatory properties of a potent histamine H4 receptor antagonist, A-940894 (4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine). EXPERIMENTAL APPROACH: We have analysed the pharmacological profile of A-940894 at mouse native, rat recombinant and human recombinant and native, histamine H4 receptors by radioligand binding, calcium mobilization, mast cell shape change, eosinophil chemotaxis assays and in the mouse model of zymosan-induced peritonitis. KEY RESULTS: A-940894 potently binds to both human and rat histamine H4 receptors and exhibits considerably lower affinity for the human histamine H1, H2 or H3 receptors. It potently blocked histamine-evoked calcium mobilization in the fluorometric imaging plate reader assays and inhibited histamine-induced shape change of mouse bone marrow-derived mast cells and chemotaxis of human eosinophils in vitro. In a mouse mast cell-dependent model of zymosan-induced peritonitis, A-940894 significantly blocked neutrophil influx and reduced intraperitoneal prostaglandin D2 levels. Finally, A-940894 has good pharmacokinetic properties, including half-life and oral bioavailability in rats and mice. CONCLUSIONS AND IMPLICATIONS: These data suggest that A-940894 is a potent and selective histamine H4 receptor antagonist with pharmacokinetic properties suitable for long-term in vivo testing and could serve as a useful tool for the further characterization of histamine H4 receptor pharmacology.

A potent and selective histamine H4 receptor antagonist with anti-inflammatory properties.[Pubmed:14722321]

J Pharmacol Exp Ther. 2004 Apr;309(1):404-13.

Histamine mediates its physiological function through binding to four known histamine receptors. Here, we describe the first selective antagonist of the histamine H4 receptor, the newest member of the histamine receptor family, and provide evidence that such antagonists have anti-inflammatory activity in vivo. 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine (JNJ 7777120) has a K(i) of 4.5 nM versus the human receptor and a pA(2) of 8.1. It is equipotent against the human, mouse, and rat receptors. It exhibits at least 1000-fold selectivity over H1, H2, or H3 receptors and has no cross-reactivity against 50 other targets. This compound has an oral bioavailability of approximately 30% in rats and 100% in dogs, with a half-life of approximately 3 h in both species. JNJ 7777120 blocks histamine-induced chemotaxis and calcium influx in mouse bone marrow-derived mast cells. In addition, it can block the histamine-induced migration of tracheal mast cells from the connective tissue toward the epithelium in mice. JNJ 7777120 significantly blocks neutrophil infiltration in a mouse zymosan-induced peritonitis model. This model is reported to be mast cell-dependent, which suggests that the compound effect may be mediated by mast cells. These results indicate that the histamine H4 receptor plays a role in the inflammatory process. Selective H4 receptor antagonists like JNJ 7777120 may have the potential to be useful in treating inflammation in humans.

The first potent and selective non-imidazole human histamine H4 receptor antagonists.[Pubmed:12954048]

J Med Chem. 2003 Sep 11;46(19):3957-60.

Following the discovery of the human histamine H4 receptor, a high throughput screen of our corporate compound collection identified compound 6 as a potential lead. Investigation of the SAR resulted in the discovery of novel compounds 10e and 10l, which are the first potent and selective histamine H4 receptor antagonists to be described.

JNJ-7777120 is a selective H4R antagonist with Ki of 4 ±1 nM, exhibits >1000-fold selectivity over the other histamin receptors.

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