jnj-7777120 and Dermatitis--Atopic

Histamine is an important endogenous signaling molecule that is involved in a number of physiological processes including allergic reactions, gastric acid secretion, neurotransmitter release, and inflammation. The biological effects of histamine are mediated by four histamine receptors with distinct functions and distribution profiles (H1-H4). The most recently discovered histamine receptor (H4) has emerged as a promising drug target for treating inflammatory diseases. A detailed understanding of the role of the H4 receptor in human disease remains elusive, in part because low sequence similarity between the human and rodent H4 receptors complicates the translation of preclinical pharmacology to humans. This review provides an overview of H4 drug discovery programs that have studied cross-species structure-activity relationships, with a focus on the functional profiling of the 2-aminopyrimidine chemotype that has advanced to the clinic for allergy, atopic dermatitis, asthma, and rheumatoid arthritis.

Topics: Aminopyridines; Animals; Arthritis, Rheumatoid; Asthma; Dermatitis, Atopic; Drug Partial Agonism; Histamine Agonists; Histamine Antagonists; Humans; Hypersensitivity; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Structure-Activity Relationship

The histamine H4 receptor (H4R), a member of the G-protein coupled receptor family, has been considered as a potential therapeutic target for treating atopic dermatitis (AD). A large number of H4R antagonists have been disclosed, but no efficient agents controlling both pruritus and inflammation in AD have been developed yet. Here, we have discovered a novel class of orally available H4R antagonists showing strong anti-itching and anti-inflammation activity as well as excellent selectivity against off-targets. A pharmacophore-based virtual screening system constructed in-house successfully identified initial hit compound 9, and the subsequent homology model-guided optimization efficiently led us to discover pyrido[2,3- e]tetrazolo[1,5- a]pyrazine analogue 48 as a novel chemotype of a potent and highly selective H4R antagonist. Importantly, orally administered compound 48 exhibits remarkable efficacy on antipruritus and anti-inflammation with a favorable pharmacokinetic (PK) profile in several mouse models of AD. Thus, these data strongly suggest that our compound 48 is a promising clinical candidate for treatment of AD.

Topics: Animals; Biological Availability; Computer Simulation; Dermatitis, Atopic; Drug Discovery; Drug Evaluation, Preclinical; Female; Histamine Antagonists; Inflammation; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Pruritus; Receptors, Histamine H4; Structure-Activity Relationship

We examined the inhibitory effect of a histamine 4 receptor (H4R) antagonist (JNJ7777120) on CCL17 and CCL22 chemokine production by human monocyte-derived Langerhans cells (MoLC) in patients with atopic dermatitis (AD) and healthy controls (HC). We confirmed the significantly higher production of both CCL17 and CCL22 in the MoLC of AD patients compared with HC. The H4R antagonist significantly inhibited the production of both CCL17 and CCL22 in the MoLC of AD patients. With regard to TLR2-signaled enhancement, peptidoglycan (PGN)-enhanced production of CCL17 and CCL22 by MoLC was inhibited by the H4R. Immunoblotting analysis demonstrated that phosphorylated p38 mitogen-activated protein kinase was induced by PGN and that this enhancement was attenuated by the application of the H4R antagonist. These data indicate that H4 signaling modulates the production of T-helper 2 chemokine in MoLC and contributes to chronic inflammation in AD patients. Our data suggest a possible novel therapeutic approach using a H4R antagonist in the treatment of patients with AD.

Topics: Cells, Cultured; Chemokine CCL17; Chemokine CCL22; Dermatitis, Atopic; Humans; Indoles; Langerhans Cells; Monocytes; p38 Mitogen-Activated Protein Kinases; Peptidoglycan; Piperazines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Signal Transduction; Staphylococcus aureus; Th2 Cells; Toll-Like Receptor 2

Natural Killer cells (NK cells) are identified as pivotal mediators in allergic skin diseases and accumulate in lesions of atopic dermatitis (AD) patients. Histamine levels are increased in these lesions and histamine is involved in chemotaxis in dendritic cells and NK cells.. The aim of this study was to determine if the histamine H4 receptor (H4R) mediates NK cell chemotaxis and whether it influences interplay between NK cells and dendritic cells during the early phase of allergic inflammation.. Chemotactic function of the H4R as well as the influence of the H4R on the cytokine profile of an NK cell-dendritic cell co-culture was studied in vitro. The effect of H4R activation on NK cell migration, NK cell-dendritic cell interaction and cytokine levels in the skin was further characterized in the murine TDI model of allergic dermatitis. Additionally, the impact of the H4R on dermal NK cells was determined in the ovalbumin (OVA)- induced allergic dermatitis model, comparing wild type and H4R knockout mice.. The selective H4R agonist ST-1006 induced NK cell chemotaxis in vitro, which was inhibited with the H4R antagonist JNJ7777120. In vivo, mice treated with TDI plus ST-1006 topically onto the ear, showed significantly enhanced ear swelling and an increased number of NK cells compared to just allergen challenged ears. CCL17 levels in the ear were also significantly increased 8h after allergen challenge. Histology revealed that the main source for increased CCL17 were dendritic cells. These effects could be blocked using the H4R antagonist JNJ7777120. In the chronic model of allergic dermatitis, OVA induced NK cell migration into lesional skin sites. The number of NK cells was lower in OVA-sensitized H4R knockout mice compared to wild type mice.. These results identify the H4R as a new target controlling NK cell migration and NK cell-dendritic cell interaction in the skin during early allergic inflammation. These results further suggest that blocking the H4R in the skin might be beneficial in diseases like AD.

Topics: Animals; Chemokine CCL17; Chemotaxis; Coculture Techniques; Dendritic Cells; Dermatitis, Atopic; Disease Models, Animal; Female; Histamine; Humans; Indoles; Killer Cells, Natural; Mice; Mice, Inbred BALB C; Mice, Knockout; Ovalbumin; Piperazines; Pyrimidines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Skin; Toluene 2,4-Diisocyanate

Topics: Animals; Dermatitis, Atopic; Disease Models, Animal; Indoles; Male; Mice; Mice, Inbred Strains; Piperazines; Pruritus; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Treatment Failure

Epidermal hyperproliferation resulting in acanthosis is an important clinical observation in patients with atopic dermatitis, and its underlying mechanisms are not completely understood.. Because increased levels of histamine are present in lesional skin, we investigated the effect of histamine, especially with regard to histamine 4 receptor (H4R) activation, on the proliferation of human and murine keratinocytes.. The expression of H4R on human and murine keratinocytes was detected by using real-time PCR. Keratinocyte proliferation was evaluated by using different in vitro cell proliferation assays, scratch assays, and measurement of the epidermal thickness of murine skin.. We detected H4R mRNA on foreskin keratinocytes and on outer root sheath keratinocytes; H4R mRNA was more abundant in keratinocytes from patients with atopic dermatitis compared with those from nonatopic donors. Stimulation of foreskin keratinocytes, atopic dermatitis outer root sheath keratinocytes, and H4R-transfected HaCaT cells with histamine and H4R agonist resulted in an increase in proliferation, which was blocked with the H4R-specific antagonist JNJ7777120. Abdominal epidermis of H4R-deficient mice was significantly thinner, and the in vitro proliferation of keratinocytes derived from H4R-deficient mice was lower compared with that seen in control mice. Interestingly, we only detected H4R expression on murine keratinocytes after stimulation with LPS and peptidoglycan.. H4R is highly expressed on keratinocytes from patients with atopic dermatitis, and its stimulation induces keratinocyte proliferation. This might represent a mechanism that contributes to the epidermal hyperplasia observed in patients with atopic dermatitis.

Topics: Animals; Cell Line; Cell Proliferation; Dermatitis, Atopic; Female; Gene Expression Regulation; Histamine; Histamine Antagonists; Humans; Indoles; Keratinocytes; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Peptidoglycan; Piperazines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4

Although histamine H1 receptor (H1R) antagonists are commonly used to treat atopic dermatitis, the treatment is not always effective. The histamine H4 receptor (H4R) was recently described as important to the pruritus in dermatitis. Here, we investigated whether the combination of a H1R antagonist plus a H4R antagonist attenuates chronic dermatitis in NC/Nga mice.. Chronic dermatitis was developed by repeated challenges with picryl chloride on the dorsal back and ear lobes. The therapeutic effects of the H1R antagonist olopatadine and H4R antagonist JNJ7777120 on scratching and the severity of dermatitis were evaluated. In addition, the mechanisms responsible for the anti-allergic effects of H1R and/or H4R antagonism were examined using bone marrow-derived mast cells (BMMC) and keratinocytes.. JNJ7777120 attenuated scratching behavior after a single administration and improved dermatitis, as assessed with clinical scores, pathology, and cytokine levels in skin lesions when administered repeatedly. These effects were augmented by combined treatment with olopatadine, having a similar therapeutic efficacy to prednisolone. JNJ7777120 inhibited dose-dependently the production of thymus and activation-regulated chemokine/CCL17 and macrophage-derived chemokine/CCL22 from antigen-stimulated BMMC. In addition, olopatadine reversed the histamine-induced reduction of semaphorin 3A mRNA in keratinocytes.. Combined treatment with H1R and H4R antagonists may have a significant therapeutic effect on chronic dermatitis through the synergistic inhibition of pruritus and skin inflammation.

Topics: Animals; Anti-Allergic Agents; Anti-Inflammatory Agents; Bone Marrow Cells; Chemokine CCL17; Chemokine CCL22; Cytokines; Dermatitis, Atopic; Dibenzoxepins; Disease Models, Animal; Down-Regulation; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Histamine Release; Immunoglobulin E; Indoles; Male; Mast Cells; Mice; Olopatadine Hydrochloride; Picryl Chloride; Piperazines; Receptors, Histamine H1; Semaphorin-3A

6-Sulpho LacNAc dendritic cells (slanDC) are a major population of human blood DC that are highly pro-inflammatory, as characterized by their outstanding capacity to produce tumour necrosis factor-α and interleukin-12 (IL-12) and to prime antigen-specific T-cell responses. SlanDC were found to be present in inflamed tissue such as atopic dermatitis, where high levels of histamine are also present. As histamine is an important regulator of allergic inflammation we investigated the role of histamine receptors, particularly the most recently identified histamine H(4) receptor (H(4) R), in modulating the pro-inflammatory function of slanDC. The expression of H(4) R was evaluated by real-time PCR and flow cytometry. Cytokine production in response to H(4) R stimulation was assessed by intracellular flow cytometric staining and enzyme-linked immunosorbent assay. We show that slanDC express the H(1) R, H(2) R and H(4) R on mRNA and the H(4) R on protein level. No differences were observed in basal H(4) R expression in patients with atopic dermatitis and psoriasis, but in atopic dermatitis patients the H(4) R was up-regulated by interferon-γ. When stimulated with lipopolysaccharide in the presence of histamine, slanDC produced substantially lower levels of the pro-inflammatory cytokines tumour necrosis factor-α and IL-12, mediated solely via the H(4) R and via the combined action of H(2) R and H(4) R, respectively. In contrast, the production of IL-10 was not affected by histamine receptor activation on slanDC. The slanDC express the H(4) R and its stimulation leads to reduced pro-inflammatory capacity of slanDC. Hence, H(4) R agonists might have therapeutic potential to down-regulate immune reactions, e.g. in allergic inflammatory skin diseases.

Topics: Amino Sugars; Cytokines; Dendritic Cells; Dermatitis, Atopic; Flow Cytometry; Histamine; Humans; Indoles; Inflammation; Interferon-gamma; Lipopolysaccharides; Methylhistamines; Piperazines; Psoriasis; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

As there is evidence for an anti-inflammatory efficacy of histamine H(4) receptor (H4R) selective antagonists, we aimed at testing the efficacy of the H4R antagonists JNJ7777120 and JNJ28307474 in comparison with histamine H(1) receptor (H1R) antagonists hydroxyzine and cetirizine for skin lesion prevention in a canine model of acute atopic dermatitis. Six atopic Maltese-beagle dogs experimentally sensitized to Dermatophagoides farinae (Df) house dust mites were selected for this study. Twenty-four hours after challenge by epicutaneous application of Df, erythematous skin lesions were scored. In this blinded, placebo and active controlled study, topical JNJ7777120 or JNJ28307474 was applied as a 1% solution before allergen challenge. The latter was also given orally at 15 mg/kg before and after allergen challenge. A 0.015% triamcinolone acetonide solution was used as a positive control. The H1R antagonists hydroxyzine and cetirizine were administered orally before challenge in a second experiment. Twenty-four hours after challenge, placebo-treated animals had a median lesional score of 2. Treatment with topical and oral JNJ28307474 resulted in a median score of 2.5. After topical administration of JNJ7777120, the median lesional score was 2. Hydroxyzine and cetirizine did also not reduce the median score of the placebo treatment. Triamcinolone acetonide prevented all dogs from having any lesions. Determination of histamine in lesions revealed that only during the initiation increased concentrations of histamine were detected. In conclusion, the preventive administration of H1R or H4R antagonists has no impact on the development of acute skin lesions in this experimental canine atopic dermatitis model.

Topics: Aging; Animals; Antigens, Dermatophagoides; Cetirizine; Dermatitis, Atopic; Dermatophagoides farinae; Disease Models, Animal; Dogs; Erythema; Female; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Hydroxyzine; Indoles; Male; Permeability; Piperazines; Skin; Skin Absorption; Triamcinolone

Effects of the histamine H(4) receptor antagonist 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine (JNJ7777120) were examined for 99 days in a long-term experimental model of pruritic dermatitis induced by repeated challenge with 2,4,6-trinitrochlorobenzene (TNCB) in HR-1 mice. Repeated application of TNCB to the back skin of mice elicited frequent scratching behavior and skin lesions at 24 h after challenge and beyond. JNJ7777120 (10 and 30 mg/kg) reduced this scratching behavior and ameliorated the skin lesions in a dose-dependent manner, whereas the histamine H(1) receptor antagonist fexofenadine had no such effect and did not reduce the inflammation score, even though dexamethasone reduced the scratching bouts. Each of the three agents reduced the increase in the serum IgE concentration induced by TNCB, but only JNJ7777120 reduced the number of mast cells in the skin lesions elicited by repeated application of TNCB. These results indicate that treatment with a H(4) receptor antagonist may be effective for amelioration of both skin inflammation and pruritus in patients with allergic dermatitis such as atopic dermatitis.

Topics: Animals; Behavior, Animal; Cell Count; Dermatitis, Atopic; Disease Models, Animal; Female; Histamine Antagonists; Immunoglobulin G; Indoles; Interleukin-4; Mast Cells; Mice; Mice, Hairless; Picryl Chloride; Piperazines; Pruritus; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; RNA, Messenger; Skin

The role of histamine H(4) receptor (H(4)R) was investigated in a T-helper type 2 (Th2)-cell-mediated mouse skin inflammation model that mimics several of the features of atopic dermatitis. Treatment with two specific H(4)R antagonists before challenge with FITC led to a significant reduction in ear edema, inflammation, mast cell, and eosinophil infiltration. This was accompanied by a reduction in the levels of several cytokines and chemokines in the ear tissue. Upon ex vivo antigen stimulation of lymph nodes, H(4)R antagonism reduced lymphocyte proliferation and IL-4, IL-5, and IL-17 levels. One explanation for this finding is that lymph nodes from animals dosed with the H(4)R antagonist, JNJ 7777120, contained a lower number of FITC-positive dendritic cells. The effect of H(4)R antagonism on dendritic cell migration in vivo may be an indirect result of the reduction in tissue cytokines and chemokines or a direct effect on chemotaxis. In addition to anti-inflammatory effects, JNJ 7777120 also significantly inhibited the pruritus shown in the model. Therefore, the dual effects of H(4)R antagonists on pruritus and Th2-cell-mediated inflammation point to their therapeutic potential for the treatment of Th2-mediated skin disorders, including atopic dermatitis.

Topics: Animals; Chemotaxis; Dendritic Cells; Dermatitis, Atopic; Disease Models, Animal; Edema; Eosinophils; Fluorescein-5-isothiocyanate; Histamine Antagonists; Indoles; Interleukin-17; Interleukin-4; Interleukin-5; Mice; Mice, Inbred BALB C; Mice, Mutant Strains; Piperazines; Pruritus; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Th2 Cells

Effects of the histamine H(4) receptor antagonist JNJ 7777120 (1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine) were tested in two models of allergic contact dermatitis. Dermatitis was induced by 2,4-dinitrochlorobenzene and toluene-2,4-diisocyanate, which differ in their Th1-Th2 profile in that way that 2,4-dinitrochlorobenzene is a classical contact allergen with a pronounced Th1-mediated inflammation, while the respiratory chemical allergen toluene-2,4-diisocyanate induces a Th2-dominated inflammation. JNJ 7777120 (15 mg/kg) administered 2 h and 30 min before and 1 h after challenge did not reduce the hapten-induced ear swelling determined 24 h after challenge. This was confirmed by histological evaluation of the ear skin. A repeated administration of the haptens to the rostral part of the back of sensitized animals resulted in a frequent scratching behaviour. An administration of JNJ 7777120 (15 mg/kg) 30 min before challenge reduced this hapten-induced scratching significantly. The H(1) receptor antagonist cetirizine also reduced the scratching bouts in sensitized mice. A combination of H(1) and H(4) receptor antagonists resulted in the strongest inhibition of scratching behaviour associated with allergic dermatitis. These results indicate that H(4) receptor antagonism fails to reduce the allergic inflammatory response but strongly inhibits allergen-induced itch. Thus, a combination of H(4) and H(1) receptor antagonism might be a new strategy to treat pruritus related to allergic diseases like atopic dermatitis.

Topics: Animals; Dermatitis, Atopic; Dose-Response Relationship, Drug; Female; Haptens; Histamine H1 Antagonists; Imidazoles; Indoles; Inflammation; Mice; Mice, Inbred BALB C; Piperazines; Pruritus; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Th2 Cells; Thiourea; Time Factors