jnj-7777120 and Pruritus

jnj-7777120 has been researched along with Pruritus* in 11 studies

Reviews

1 review(s) available for jnj-7777120 and Pruritus

ArticleYear
A new generation of anti-histamines: Histamine H4 receptor antagonists on their way to the clinic.
    Current opinion in drug discovery & development, 2009, Volume: 12, Issue:5

    At the turn of the millennium, the DNA sequence encoding the histamine H4 receptor (H4R) was identified in data from human genome databases. Considering the clinical importance of H1R and H2R ligands, and the clinical trials that are ongoing for H3R ligands, the latest addition to the histamine receptor family was noted with interest by the pharmaceutical industry. Initial studies describing the expression of the H4R, and the activity of this receptor in (patho)physiology, suggested that the H4R played a role in the immune system. The introduction of the reference H4R antagonist JNJ-7777120 (Johnson & Johnson Pharmaceutical Research & Development LLC/Abbott Laboratories), and proof of the efficacy of this agent in models of asthma, allergic rhinitis and pruritus, highlighted the H4R as a novel drug target. The first clinical candidates targeting the H4R have been identified, and new H4R antagonists are expected to enter the clinic in the near future.

    Topics: Animals; Anti-Allergic Agents; Asthma; Disease Models, Animal; Drug Design; Drug Discovery; Histamine Antagonists; Humans; Indoles; Molecular Structure; Piperazines; Pruritus; Pyrimidines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Structure-Activity Relationship

2009

Other Studies

10 other study(ies) available for jnj-7777120 and Pruritus

ArticleYear
Discovery of a Novel Highly Selective Histamine H4 Receptor Antagonist for the Treatment of Atopic Dermatitis.
    Journal of medicinal chemistry, 2018, 04-12, Volume: 61, Issue:7

    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

2018
Persistent Extracellular Signal-Regulated Kinase Activation by the Histamine H4 Receptor in Spinal Neurons Underlies Chronic Itch.
    The Journal of investigative dermatology, 2018, Volume: 138, Issue:8

    Transient extracellular signal-regulated kinase (ERK) activation in the spinal cord triggers histamine-induced acute itch. However, whether persistent ERK activation plays an important role in chronic itch development remains unclear. This study investigated the role of spinal ERK activation in chronic itch. The results showed that repetitive DNFB painting on the nape of mice evoked not only initial scratching but also sustained, spontaneous scratching. In addition, DNFB induced itching rather than nociception, as demonstrated using a cheek model. Furthermore, ERK was persistently activated in the spinal cord of DNFB-treated mice, and the intrathecal inhibition of phosphorylation of ERK suppressed both spontaneous itching and ERK activation. ERK activation was observed in neurons but not in glia cells during chronic itch development. Finally, DNFB-induced spontaneous itching behavior and ERK activation were largely inhibited by the histamine H4 receptor antagonist JNJ7777120 but not by the H1 receptor antagonist chlorpheniramine. Our results indicate that persistent ERK activation via the histamine H4 receptor in spinal neurons underlies DNFB-induced chronic itch.

    Topics: Animals; Behavior, Animal; Chronic Disease; Dinitrofluorobenzene; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Histamine H1 Antagonists; Humans; Indoles; Male; MAP Kinase Signaling System; Mice; Mice, Inbred ICR; Nociception; Piperazines; Pruritus; Receptors, Histamine H1; Receptors, Histamine H4; Sensory Receptor Cells; Skin; Spinal Cord

2018
Discovery and SAR of 6-alkyl-2,4-diaminopyrimidines as histamine Hâ‚„ receptor antagonists.
    Journal of medicinal chemistry, 2014, Mar-27, Volume: 57, Issue:6

    This report discloses the discovery and SAR of a series of 6-alkyl-2-aminopyrimidine derived histamine H4 antagonists that led to the development of JNJ 39758979, which has been studied in phase II clinical trials in asthma and atopic dermatitis. Building on our SAR studies of saturated derivatives from the indole carboxamide series, typified by JNJ 7777120, and incorporating knowledge from the tricyclic pyrimidines led us to the 6-alkyl-2,4-diaminopyrimidine series. A focused medicinal chemistry effort delivered several 6-alkyl-2,4-diaminopyrimidines that behaved as antagonists at both the human and rodent H4 receptor. Further optimization led to a panel of antagonists that were profiled in animal models of inflammatory disease. On the basis of the preclinical profile and efficacy in several animal models, JNJ 39758979 was selected as a clinical candidate; however, further development was halted during phase II because of the observation of drug-induced agranulocytosis (DIAG) in two subjects.

    Topics: Animals; Arthritis; Collagen; Dogs; Drug Design; Drug Discovery; Histamine; Histamine Antagonists; Indicators and Reagents; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Models, Molecular; Pruritus; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Structure-Activity Relationship; Tumor Necrosis Factor-alpha

2014
Histamine H(4) receptor antagonists ineffective against itch and skin inflammation in atopic dermatitis mouse model.
    The Journal of investigative dermatology, 2014, Volume: 134, Issue:2

    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

2014
Histamine H(4) receptor antagonist reduces dermal inflammation and pruritus in a hapten-induced experimental model.
    European journal of pharmacology, 2011, Sep-30, Volume: 667, Issue:1-3

    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

2011
Histamine H1, H3 and H4 receptors are involved in pruritus.
    Neuroscience, 2011, Sep-08, Volume: 190

    Histamine has long been recognised as a classical inducer of pruritus. However, the specific mechanism of histamine-induced itch has still not been fully understood. The H1 and H4 receptor appear to be key components in the induction of itch. The specific role of the H3 receptor in histamine-induced itch remains unclear. The aim of our study was to investigate the role of the four known histamine receptors (H1-4) in acute itch in mice. Intradermal injection of the selective H3R inverse agonist pitolisant induced strong itch in mice. Pitolisant (50 nmol/injection)-induced pruritus could be completely blocked by a combined treatment with the H1R antagonist cetirizine (15 mg/kg) and the H4R antagonist JNJ 7777120 (15 mg/kg), whereas the H2R antagonist ranitidine (15 mg/kg) failed to inhibit the scratch response. Next, expression and function of histamine receptors on sensory neurons isolated from dorsal root ganglia of mice were investigated. As the itch sensation results from the excitation of sensory nerves in the skin, we further focused on skin specific sensory neurons. Therefore, neurons were retrograde labelled from the skin by means of a fluorescent tracer. Expression of H1R, H3R and H4R on skin innervating sensory neurons was detected. By single-cell calcium imaging, it was demonstrated that histamine induces a calcium increase in a subset of (skin-specific) sensory neurons via activation of the H1R and H4R as well as inhibition of the H3R. It is assumed that the decreased threshold in response to H3R antagonism activates H1R and H4R on sensory neurons, which in turn results in the excitation of histamine-sensitive afferents and therefore elicits the sensation of itch.

    Topics: Animals; Calcium; Female; Ganglia, Spinal; Histamine Agents; Indoles; Mice; Piperazines; Pruritus; Ranitidine; Receptors, Histamine; Sensory Receptor Cells; Skin

2011
The histamine H4 receptor mediates inflammation and pruritus in Th2-dependent dermal inflammation.
    The Journal of investigative dermatology, 2010, Volume: 130, Issue:4

    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

2010
Histamine H4 receptor antagonism reduces hapten-induced scratching behaviour but not inflammation.
    Experimental dermatology, 2009, Volume: 18, Issue:1

    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

2009
Expression of histamine H4 receptor in human epidermal tissues and attenuation of experimental pruritus using H4 receptor antagonist.
    The Journal of toxicological sciences, 2009, Volume: 34, Issue:4

    Many medicines exist which can cause pruritus (itching) as "serious adverse events." Many severe pruritic conditions respond poorly to histamine H1 receptor antagonists; there is no generally accepted antipruritic treatment. Recently described histamine H4 receptors are expressed in haematopoietic cells and have been linked to the pathology of allergy and asthma. We previously reported their expression in human dermal fibroblasts; in this study we have investigated H4 receptor expression in human epidermal tissue and found it to be greater in keratinocytes in the epidermal upper layer than in the lower layer. We have also investigated the effect of histamine H4 receptor antagonists on histamine H1 receptor antagonist-resistant pruritus using a mouse model. Scratching behavior was induced by histamine (300 nmol) or substance P (100 nmol) injected intradermally into the rostral part of the back of each mouse. Fexofenadine, a histamine H1 receptor antagonist, reduced scratching induced by histamine but not by substance P, whereas JNJ7777120, a histamine H4 receptor antagonist, significantly reduced both histamine- and substance P-induced scratching. These results suggest that H4 receptor antagonists may be useful for treatment of H1 receptor antagonist-resistant pruritus.

    Topics: Animals; Disease Models, Animal; Epidermis; Histamine; Histamine Antagonists; Humans; Indoles; Keratinocytes; Male; Mice; Mice, Inbred ICR; Piperazines; Pruritus; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Substance P

2009
Histamine H4 receptor antagonists are superior to traditional antihistamines in the attenuation of experimental pruritus.
    The Journal of allergy and clinical immunology, 2007, Volume: 119, Issue:1

    Histamine is a potent mediator of itch in humans, yet histamine H(1) receptor antagonists have been shown to be of limited use in the treatment of certain chronic pruritic diseases. The histamine H(4) receptor is a recently described histamine receptor, expressed on hematopoietic cells, linked to the pathology of allergy and asthma.. The contribution of the novel histamine H(4) receptor to histaminergic and allergic pruritus was investigated.. Histamine and a selective histamine H(4) receptor agonist caused scratching responses in mice, which were almost completely attenuated in histamine H(4) receptor knockout mice or by pretreatment with the selective histamine H(4) receptor antagonist, JNJ 7777120. Pruritus induced by allergic mechanisms was also potently inhibited with histamine H(4) receptor antagonist treatment or in histamine H(4) receptor knockout mice. In all cases, the inhibitory effect of histamine H(4) receptor antagonist was greater than those observed with histamine H(1) receptor antagonists. The histamine H(4) receptor-mediated pruritus was shown to be independent of mast cells or other hematopoietic cells and may result from actions on peripheral neurons.. These results demonstrate that the histamine H(4) receptor is involved in pruritic responses in mice to a greater extent than the histamine H(1) receptor.. Histamine H(4) receptor antagonists may have therapeutic utility for treating chronic pruritic diseases in humans where histamine H(1) receptor antagonists are not effective.

    Topics: Animals; Disease Models, Animal; Edema; Female; Foot; Histamine; Histamine Agonists; Histamine Antagonists; Indoles; Mast Cells; Mice; Mice, Inbred BALB C; Mice, Knockout; Piperazines; Pruritus; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H4

2007