Publications by authors named "Paul J Dunford"

22 Publications

  • Page 1 of 1

The CSF-1-receptor inhibitor, JNJ-40346527 (PRV-6527), reduced inflammatory macrophage recruitment to the intestinal mucosa and suppressed murine T cell mediated colitis.

PLoS One 2019 11;14(11):e0223918. Epub 2019 Nov 11.

Janssen Research & Development, LLC, Pennsylvania, United States of America.

Background & Aims: Originally believed to be primarily a disorder of T-cell signaling, evidence shows that macrophage-lineage cells also contribute to the pathogenesis of Crohn's disease (CD). Colony stimulating factor-1 (CSF-1) is a key regulator of the macrophage lineage, but its role in CD has not been well established. We examined transcriptional data from CD mucosa for evidence of CSF-1 pathway activation and tested JNJ-40346527 (PRV-6527), a small molecule inhibitor of CSF-1 receptor kinase (CSF-1R), for its ability to inhibit disease indices in murine colitis.

Methods: A CSF-1 pathway gene set was created from microarray data of human whole blood cultured ex vivo with CSF-1 and compared to a TNFα-induced gene set generated from epithelial-lineage cells. Gene set variation analysis was performed using existing Crohn's mucosa microarray data comparing patients who either responded or failed to respond to anti-TNFα therapy. Commencing day 14 or day 21, mice with T-cell transfer colitis were treated with vehicle or JNJ-40346527 until study termination (day 42). Endpoints included colon weight/length ratios and histopathology scores, and macrophage and T cells were assessed by immunohistochemistry. Mucosal gene expression was investigated using RNAseq.

Results: Both the CSF-1 and the TNFα gene sets were enriched in the colonic mucosal transcriptomes of Crohn's disease and in mouse colitis, and expression of both gene sets was highest in patients who did not respond to anti-TNFα therapy. In these patients neither set was reduced by therapy. In the mouse model, JNJ-40346527 inhibited the increase in colon weight/length ratio by ∼50%, reduced histological disease scores by ∼60%, and reduced F4/80+ mononuclear cell and CD3+ lymphocyte numbers. RNAseq analysis confirmed the CSF-1 gene set was sharply reduced in treated mice, as were gene sets enriched in "M1" inflammatory and "M0" resident macrophages and in activated T cells.

Conclusions: CSF-1 biology is activated in Crohn's disease and in murine T cell transfer colitis. Inhibition of CSF-1R by JNJ-40346527 was associated with attenuated clinical disease scores and reduced inflammatory gene expression in mice. These data provide rationale for testing JNJ-40346527 (PRV-6527) in human inflammatory bowel disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223918PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844469PMC
March 2020

Toreforant, an orally active histamine H-receptor antagonist, in patients with active rheumatoid arthritis despite methotrexate: mechanism of action results from a phase 2, multicenter, randomized, double-blind, placebo-controlled synovial biopsy study.

Inflamm Res 2019 Apr 9;68(4):261-274. Epub 2019 Feb 9.

Immunology Clinical Development, Janssen Research & Development LLC, Spring House, PA, USA.

Objective/design: In a double-blind, placebo-controlled, multiple-dose study, we assessed the molecular mechanism of action of the selective histamine-4-receptor antagonist toreforant.

Patients/treatment: Patients with active rheumatoid arthritis (RA) despite methotrexate were randomized (3:1) to toreforant 30 mg/day (weeks 0-52) or placebo (weeks 0-12) followed by toreforant 30 mg/day (weeks 12-52).

Methods: Primary biomarker analyses comprised 39 different proteins/mRNA transcripts measured in synovial biopsy (n = 39) and/or time-matched serum (n = 15) samples collected at baseline and week 6. Clinical response was assessed using C-reactive protein-based 28-joint disease activity scores. Data were summarized using descriptive statistics.

Results: Among 21 randomized, treated patients (toreforant-16, placebo-5), 18 (toreforant-13, placebo-5) completed the 12-week double-blind period (none completed open-label treatment) prior to the early study termination. Biomarker profiling indicated potential modest effects of toreforant on gene expression of histamine-1-receptor, tumor necrosis factor-alpha, and interleukin-8 in synovium. Potential trends between biomarkers and clinical response were observed with synovial monocyte chemoattractant protein-4 and phosphorylated extracellular-signal-regulated kinases and serum matrix metalloproteinase-3. Minimal synovial gene expression of interleukins-17A and 17F was detected.

Conclusions: While clear biomarker signals associated with toreforant pharmacology in RA patients were not identified, modest associations between biomarkers and clinical response were noted. Synovial expression of interleukins-17A/17F was minimal. Limited sample size warrants cautious interpretation.
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http://dx.doi.org/10.1007/s00011-019-01218-yDOI Listing
April 2019

Clinical Development of Histamine H Receptor Antagonists.

Handb Exp Pharmacol 2017 ;241:301-320

Janssen Research & Development, LLC, San Diego, CA, 92121, USA.

The discovery of the histamine H receptor (HR) 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 HR relative to other histamine receptors. The discovery of the selective HR antagonist JNJ 7777120 was vital for showing a role for the HR 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 HR 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 HR 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 HR 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 HR antagonists can be beneficial in treating atopic dermatitis and pruritus.
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http://dx.doi.org/10.1007/164_2016_130DOI Listing
October 2017

The histamine H₄ receptor antagonist, JNJ 39758979, is effective in reducing histamine-induced pruritus in a randomized clinical study in healthy subjects.

J Pharmacol Exp Ther 2014 Jul 9;350(1):181-7. Epub 2014 May 9.

Janssen Research & Development, LLC, San Diego, California (A.K., B.C., P.J.D., A.J.G., X.L.X., R.L.T.); Parexel International, London, United Kingdom (K.F.); and Janssen Research & Development, LLC, Spring House, Pennsylvania (Y.X., B.Z.)

The histamine H4 receptor (H4R) is a promising target for the treatment of pruritus. A clinical study was conducted to evaluate the safety and efficacy of the H4R antagonist, JNJ 39758979 [(R)-4-(3-amino-pyrrolidin-1-yl)-6-isopropyl-pyrimidin-2-ylamine], on histamine-induced pruritus in healthy subjects. A single oral dose of 600 mg JNJ 39758979, 10 mg cetirizine, or placebo was administered in a randomized, three-period, double-blind, crossover study. Treatment periods were separated by 22-day washout periods. A histamine challenge was administered on day -1 and at 2 and 6 hours postdose on day 1 of each treatment period. The primary efficacy endpoint was the area under the curve (AUC) of pruritus score 0-10 minutes after the histamine challenge. Secondary efficacy endpoints included wheal and flare areas assessed 10 minutes after the histamine challenge. Safety was assessed for all subjects. Of the 24 enrolled subjects, 23 individuals completed the study. One subject withdrew after completing two treatment periods. Due to a carryover effect of JNJ 39758979, only treatment period 1 was used for pruritus-related evaluations. Compared with placebo, the reduction of the AUC of pruritus score was significant for JNJ 39758979 at 2 hours (P = 0.0248) and 6 hours (P = 0.0060), and for cetirizine at 6 hours (P = 0.0417). In all treatment periods, JNJ 39758979 did not demonstrate a significant decrease in wheal or flare at either time point, although a significant reduction was achieved with cetirizine at 2 and 6 hours (P < 0.0001). Adverse eventss reported in >1 patient with JNJ 39758979 were headache (9%) and nausea (13%). In conclusion, JNJ 39758979 was effective in inhibiting histamine-induced pruritus in healthy subjects.
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http://dx.doi.org/10.1124/jpet.114.215749DOI Listing
July 2014

Clinical and preclinical characterization of the histamine H(4) receptor antagonist JNJ-39758979.

J Pharmacol Exp Ther 2014 May 18;349(2):176-84. Epub 2014 Feb 18.

Janssen Research & Development, L.L.C., San Diego, California.

The histamine H4 receptor (H(4)R) has been shown to have preclinical involvement in both inflammatory and pruritic responses. JNJ-39758979 [(R)-4-(3-amino-pyrrolidin-1-yl)-6-isopropyl-pyrimidin-2-ylamine] is a potent and selective H(4)R antagonist with a Ki at the human receptor of 12.5 ± 2.6 nM and greater than 80-fold selectivity over other histamine receptors. The compound also exhibited excellent selectivity versus other targets. JNJ-39758979 showed dose-dependent activity in models of asthma and dermatitis consistent with other H(4)R antagonists. Preclinical toxicity studies of up to 6 months in rats and 9 months in monkeys indicated an excellent safety profile, supporting the clinical testing of the compound. An oral formulation of JNJ-39758979 was studied in a phase 1 human volunteer study to assess safety, pharmacokinetics, and pharmacodynamics. The compound was well tolerated, with the exception of dose-dependent nausea, and no safety issues were noted in the phase 1 study. JNJ-39758979 exhibited good pharmacokinetics upon oral dosing with a plasma half-life of 124-157 hours after a single oral dose. In addition, dose-dependent inhibition of histamine-induced eosinophil shape change was detected, suggesting that the H4R was inhibited in vivo. In conclusion, JNJ-39758979 is a potent and selective H(4)R antagonist that exhibited good preclinical and phase 1 safety in healthy volunteers with evidence of a pharmacodynamics effect in humans.
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http://dx.doi.org/10.1124/jpet.113.211714DOI Listing
May 2014

Discovery and SAR of 6-alkyl-2,4-diaminopyrimidines as histamine H₄ receptor antagonists.

J Med Chem 2014 Mar 21;57(6):2429-39. Epub 2014 Feb 21.

Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.

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.
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http://dx.doi.org/10.1021/jm401727mDOI Listing
March 2014

The histamine H4 receptor mediates inflammation and Th17 responses in preclinical models of arthritis.

Ann Rheum Dis 2014 Mar 14;73(3):600-8. Epub 2013 Oct 14.

Department of Immunology, Janssen Research & Development, , San Diego, California, USA.

Objective: The histamine H4 receptor (H4R) has been shown to drive inflammatory responses in models of asthma, colitis and dermatitis, and in these models it appears to affect both innate and adaptive immune responses. In this study, we used both H4R-deficient mice and a specific H4R antagonist, JNJ 28307474, to investigate the involvement of the H4R in mouse arthritis models.

Methods: H4R-deficient mice and wild-type mice administered the H4R antagonist were studied in models of collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis (CIA). The impact on Th17 cells was assessed by restimulation of inguinal lymphocytes in the disease or immunisation models and with in vitro stimulation of whole blood.

Results: Both H4R-deficient mice and mice treated with the H4R antagonist exhibited reduced arthritis disease severity in both CAIA and CIA models. This was evident from the reduction in disease score and in joint histology. In the CIA model, treatment with the H4R antagonist reduced the number of interleukin (IL)-17 positive cells in the lymph node and the total production of IL-17. Th17 cell development in vivo was reduced in H4R-deficient mice or in mice treated with an H4R antagonist. Finally, treatment of both mouse and human blood with an H4R antagonist reduced the production of IL-17 when cells were stimulated in vitro.

Conclusions: These results implicate the H4R in disease progression in arthritis and in the production of IL-17 from Th17 cells. This work supports future clinical exploration of H4R antagonists for the treatment of rheumatoid arthritis.
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http://dx.doi.org/10.1136/annrheumdis-2013-203832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4151522PMC
March 2014

Antagonism of the histamine H4 receptor reduces LPS-induced TNF production in vivo.

Inflamm Res 2013 Jun 27;62(6):599-607. Epub 2013 Mar 27.

Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

Objective: Antagonism of the histamine H4 receptor (H4R) has been shown to be anti-inflammatory in a number of preclinical disease models, however the exact mechanisms behind this are still being uncovered. In vitro, the receptor interacts with TLR and impacts inflammatory mediator production from a number of different cell types. Here it is shown that this interaction also occurs in vivo.

Materials And Methods: Wild-type and H4R deficient BALB/c mice received an i.p. injection of LPS in PBS in conjunction with p.o. JNJ 7777120 or JNJ 28307474 (H4R antagonists). Two hours later blood was collected and TNF was measured.

Results: Two different H4R antagonists inhibited LPS-induced TNF production in mice and this production was also reduced in H4R-deficient mice. The TNF mRNA analysis showed that the major source of the cytokine was the liver and not blood, and that the H4R antagonist only reduced the expression levels in the liver. Depletion or inactivation of macrophages reduced the TNF levels and eliminated the H4R sensitivity. Treatment with an H4R antagonist also reduced LPS-induced liver injury and blocked LPS-enhanced lung inflammation in mice.

Conclusion: The data support an interaction between H4R and TLR activation in vivo that can drive inflammatory responses.
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http://dx.doi.org/10.1007/s00011-013-0612-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654183PMC
June 2013

Histamine H4 receptor antagonism diminishes existing airway inflammation and dysfunction via modulation of Th2 cytokines.

Respir Res 2010 Jun 24;11:86. Epub 2010 Jun 24.

Immunology, Johnson & Johnson Pharmaceutical Research & Development, LLC San Diego, California, USA.

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.

Results: Therapeutic H4R antagonism inhibited T cell infiltration in to the lung and decreased Th2 cytokines IL-13 and IL-5. IL-13 dependent remodeling parameters such as GCH and lung collagen were reduced. Intervention with H4R antagonist also improved measures of central and peripheral airway dysfunction.

Conclusions: These data demonstrate that therapeutic H4R antagonism can significantly ameliorate allergen induced, Th2 cytokine driven pathologies such as lung remodeling and airway dysfunction. The ability of H4R antagonists to affect these key manifestations of asthma suggests their potential as novel human therapeutics.
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http://dx.doi.org/10.1186/1465-9921-11-86DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2914735PMC
June 2010

Leukotriene A(4) hydrolase inhibition attenuates allergic airway inflammation and hyperresponsiveness.

Am J Respir Crit Care Med 2010 May 28;181(9):899-907. Epub 2010 Jan 28.

Immunology, Johnson & Johnson PRD, 3210 Merryfield Row, San Diego, CA 92121, USA.

Rationale: Allergic asthma is characterized by reversible airway obstruction, lung inflammation, and airway hyperresponsiveness (AHR). Previous studies using leukotriene B(4) (LTB(4)) receptor 1-deficient mice and adoptive transfer experiments have suggested that LTB(4) plays a role in lung inflammation and AHR.

Objectives: In this study, we used a leukotriene A(4) hydrolase (LTA(4)H) inhibitor as a pharmacological tool to directly examine the role of LTB(4) in a mast cell-dependent murine model of allergic airway inflammation.

Methods: We used the forced oscillation technique to test the effects of an LTA(4)H inhibitor dosed during the challenge phase on AHR. Lung tissue and lavage were collected for analysis.

Measurements And Main Results: Treatment with an LTA(4)H inhibitor improved multiple parameters encompassing AHR and lung function. Significant decreases in inflammatory leukocytes, cytokines, and mucin were observed in the lung lumen. Serum levels of antigen-specific IgE and IgG1 were also decreased. Labeled antigen uptake by lung dendritic cells and subsequent trafficking to draining lymph nodes and the lung were decreased on LTA(4)H inhibitor treatment. Provocatively, inhibition of LTA(4)H increased lipoxin A(4) levels in lung lavage fluid.

Conclusions: These data suggest that LTB(4) plays a key role in driving lung inflammation and AHR. Mechanistically, we provide evidence that inhibition of LTA(4)H, affects recruitment of both CD4(+) and CD8(+) T cells, as well as trafficking of dendritic cells to draining lymph nodes, and may beneficially modulate other pro- and antiinflammatory eicosanoids in the lung. Inhibition of LTA(4)H is thus a potential therapeutic strategy that could modulate key aspects of asthma.
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http://dx.doi.org/10.1164/rccm.200807-1158OCDOI Listing
May 2010

The role of histamine in asthma.

Adv Exp Med Biol 2010 ;709:53-66

Department of Immunology, Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, California 92121, USA.

Histamine is a ubiquitous inflammatory mediator intimately associated with the pathology of allergy. Traditional antihistamines, targeting the histamine H1 receptor, have failed to demonstrate a significant role for histamine in asthma. Novel immunomodulatory roles for histamine and the discovery of a novel histamine receptor, the histamine H4 receptor, have resulted in a reassessment of its importance in asthma.
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http://dx.doi.org/10.1007/978-1-4419-8056-4_6DOI Listing
July 2011

The histamine H4 receptor mediates inflammation and pruritus in Th2-dependent dermal inflammation.

J Invest Dermatol 2010 Apr 12;130(4):1023-33. Epub 2009 Nov 12.

Department of Immunology, Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, California 92121, USA.

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.
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http://dx.doi.org/10.1038/jid.2009.358DOI Listing
April 2010

Identification of a potent, selective, and orally active leukotriene a4 hydrolase inhibitor with anti-inflammatory activity.

J Med Chem 2008 Jul 28;51(14):4150-69. Epub 2008 Jun 28.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.

LTA 4H is a ubiquitously distributed 69 kDa zinc-containing cytosolic enzyme with both hydrolase and aminopeptidase activity. As a hydrolase, LTA 4H stereospecifically catalyzes the transformation of the unstable epoxide LTA 4 to the diol LTB 4, a potent chemoattractant and activator of neutrophils and a chemoattractant of eosinophils, macrophages, mast cells, and T cells. Inhibiting the formation of LTB 4 is expected to be beneficial in the treatment of inflammatory diseases such as inflammatory bowel disease (IBD), asthma, and atherosclerosis. We developed a pharmacophore model using a known inhibitor manually docked into the active site of LTA 4H to identify a subset of compounds for screening. From this work we identified a series of benzoxazole, benzthiazole, and benzimidazole inhibitors. SAR studies resulted in the identification of several potent inhibitors with an appropriate cross-reactivity profile and excellent PK/PD properties. Our efforts focused on further profiling JNJ 27265732, which showed encouraging efficacy in a disease model relevant to IBD.
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http://dx.doi.org/10.1021/jm701575kDOI Listing
July 2008

A novel B-RAF inhibitor blocks interleukin-8 (IL-8) synthesis in human melanoma xenografts, revealing IL-8 as a potential pharmacodynamic biomarker.

Mol Cancer Ther 2008 Mar;7(3):492-9

Department of Immunology, Johnson & Johnson Pharmaceutical Research & Development LLC, La Jolla, CA 92121, USA.

B-RAF mutations have been identified in the majority of melanoma and a large fraction of colorectal and papillary thyroid carcinoma. Drug discovery efforts targeting mutated B-RAF have yielded several interesting molecules, and currently, three compounds are undergoing clinical evaluation. Inhibition of B-RAF in animal models leads to a slowing of tumor growth and, in some cases, tumor reduction. Described within is a novel series of diaryl imidazoles with potent, single-digit nanomolar, anti-B-RAF activity. One compound from this series has been detailed here and has been shown to block B-RAF(V600E)-dependent extracellular signal-regulated kinase 1/2 phosphorylation in SK-MEL-28 melanoma cells as well as soft agar colony formation and proliferation. Importantly, interleukin-8 (IL-8) was identified by quantitative real-time PCR and ELISA as a product of the elevated mitogen-activated protein kinase signaling in these cells. Plasma concentrations of IL-8 in mice bearing melanoma xenografts were significantly reduced following exposure to B-RAF inhibitors. Taken together, these data suggest that IL-8 could serve as a tractable clinical biomarker.
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http://dx.doi.org/10.1158/1535-7163.MCT-07-0307DOI Listing
March 2008

The role of histamine H1 and H4 receptors in allergic inflammation: the search for new antihistamines.

Nat Rev Drug Discov 2008 Jan;7(1):41-53

Johnson & Johnson Pharmaceutical Research & Development, L.L.C. San Diego, California 92121, USA.

Histamine has a key role in allergic inflammatory conditions. The inflammatory responses resulting from the liberation of histamine have long been thought to be mediated by the histamine H1 receptor, and H1-receptor antagonists--commonly known as antihistamines--have been used to treat allergies for many years. However, the importance of histamine in the pathology of conditions such as asthma and chronic pruritus may have been underestimated. Here, we review accumulating evidence suggesting that histamine indeed has roles in inflammation and immune function modulation in such diseases. In particular, the discovery of a fourth histamine receptor (H4) and its expression on numerous immune and inflammatory cells has prompted a re-evaluation of the actions of histamine, suggesting a new potential for H4-receptor antagonists and a possible synergy between H1 and H4-receptor antagonists in targeting various inflammatory conditions.
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http://dx.doi.org/10.1038/nrd2465DOI Listing
January 2008

Anti-inflammatory activity of a potent, selective leukotriene A4 hydrolase inhibitor in comparison with the 5-lipoxygenase inhibitor zileuton.

J Pharmacol Exp Ther 2007 Jun 19;321(3):1154-60. Epub 2007 Mar 19.

Johnson and Johnson Pharmaceutical Research and Development LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.

Leukotriene A(4) hydrolase (LTA(4)H) catalyzes production of the proinflammatory lipid mediator, leukotriene (LT) B(4), which is implicated in a number of inflammatory diseases. We have identified a potent and selective inhibitor of both the epoxide hydrolase and aminopeptidase activities of recombinant human LTA(4)H (IC(50), approximately 10 nM). In a murine model of arachidonic acid-induced ear inflammation, the LTA(4)H inhibitor, JNJ-26993135 (1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidine-4-carboxylic acid), dose-dependently inhibited ex vivo LTB(4) production in blood, in parallel with dose-dependent inhibition of neutrophil influx (ED(50), 1-3 mg/kg) and ear edema. In murine whole blood and in zymosan-induced peritonitis, JNJ-26993135 selectively inhibited LTB(4) production, without affecting cysteinyl leukotriene production, while maintaining or increasing production of the anti-inflammatory mediator, lipoxin (LX) A(4). The 5-lipoxygenase (5-LO) inhibitor zileuton showed inhibition of LTB(4), LTC(4), and LXA(4) production. Although zileuton inhibited LTB(4) production in the peritonitis model more effectively than the LTA(4)H inhibitor, the influx of neutrophils into the peritoneum after 1 and 2 h was significantly higher in zileuton- versus JNJ-26993135-treated animals. This difference may have been mediated by the increased LXA(4) levels in the presence of the LTA(4)H inhibitor. The selective inhibition of LTB(4) production by JNJ-26993135, while increasing levels of the anti-inflammatory mediator, LXA(4), may translate to superior therapeutic efficacy versus 5-LO or 5-LO-activating protein inhibitors in LTB(4)-mediated inflammatory diseases.
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http://dx.doi.org/10.1124/jpet.106.115436DOI Listing
June 2007

The histamine H(4) receptor: a novel modulator of inflammatory and immune disorders.

Pharmacol Ther 2007 Mar 28;113(3):594-606. Epub 2006 Dec 28.

Johnson & Johnson Pharmaceutical Research and Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

All 4 known histamine receptors (H(1)R, H(2)R, H(3)R and H(4)R) have been used or proposed as therapeutic targets for varied diseases. This article reviews the recent progress in understanding the function of the recently described histamine receptor H(4)R in a variety of immune responses and the potential therapeutic value of H(4)R antagonists. The H(4)R is expressed primarily on cells involved in inflammation and immune response. It has effects on chemotaxis, as well as cytokine and chemokine production of mast cells, eosinophils, dendritic cells, and T cells. H(4)R antagonists, JNJ 7777120 and JNJ 10191584 (also known as VUF 6002) have been developed with excellent affinity and selectivity towards human and rodent H(4)R. These antagonists also demonstrate efficacy as anti-inflammatory agents in vivo. H(4)R antagonists have shown promising activity in down-regulating immune responses in a range of animal disease models including acute inflammation, hapten-mediated colitis, and allergic airway inflammation. Due to its distribution on immune cells and its proven role in inflammatory functions, the H(4)R appears to be a therapeutic target for the treatment of a variety of immune disorders.
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http://dx.doi.org/10.1016/j.pharmthera.2006.11.008DOI Listing
March 2007

Histamine H4 receptor antagonists are superior to traditional antihistamines in the attenuation of experimental pruritus.

J Allergy Clin Immunol 2007 Jan 13;119(1):176-83. Epub 2006 Oct 13.

Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, CA 92121, USA.

Background: 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.

Objective: The contribution of the novel histamine H(4) receptor to histaminergic and allergic pruritus was investigated.

Results: 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.

Conclusion: 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.

Clinical Implications: 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.
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http://dx.doi.org/10.1016/j.jaci.2006.08.034DOI Listing
January 2007

The histamine H4 receptor mediates allergic airway inflammation by regulating the activation of CD4+ T cells.

J Immunol 2006 Jun;176(11):7062-70

Johnson & Johnson Pharmaceutical Research and Development, San Diego, CA 92121, USA.

Histamine is an important inflammatory mediator that is released in airways during an asthmatic response. However, current antihistamine drugs are not effective in controlling the disease. The discovery of the histamine H4 receptor (H4R) prompted us to reinvestigate the role of histamine in pulmonary allergic responses. H4R-deficient mice and mice treated with H4R antagonists exhibited decreased allergic lung inflammation, with decreases in infiltrating lung eosinophils and lymphocytes and decreases in Th2 responses. Ex vivo restimulation of T cells showed decreases in IL-4, IL-5, IL-13, IL-6, and IL-17 levels, suggesting that T cell functions were disrupted. In vitro studies indicated that blockade of the H4R on dendritic cells leads to decreases in cytokine and chemokine production and limits their ability to induce Th2 responses in T cells. This work suggests that the H4R can modulate allergic responses via its influence on T cell activation. The study expands the known influences of histamine on the immune system and highlights the therapeutic potential of H4R antagonists in allergic conditions.
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http://dx.doi.org/10.4049/jimmunol.176.11.7062DOI Listing
June 2006

Preparation and biological evaluation of indole, benzimidazole, and thienopyrrole piperazine carboxamides: potent human histamine h(4) antagonists.

J Med Chem 2005 Dec;48(26):8289-98

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.

Three series of H(4) receptor ligands, derived from indoly-2-yl-(4-methyl-piperazin-1-yl)-methanones, have been synthesized and their structure-activity relationships evaluated for activity at the H(4) receptor in competitive binding and functional assays. In all cases, substitution of small lipophilic groups in the 4 and 5-positions led to increased activity in a [(3)H]histamine radiolabeled ligand competitive binding assay. In vitro metabolism and initial pharmacokinetic studies were performed on selected compounds leading to the identification of indole 8 and benzimidazole 40 as potent H(4) antagonists with the potential for further development. In addition, both 8 and 40 demonstrated efficacy in in vitro mast cell and eosinophil chemotaxis assays.
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http://dx.doi.org/10.1021/jm0502081DOI Listing
December 2005

Inhibitory effects of histamine H4 receptor antagonists on experimental colitis in the rat.

Eur J Pharmacol 2005 Oct 6;522(1-3):130-8. Epub 2005 Oct 6.

Department of Comparative Physiology, Szeged University, Hungary.

The histamine H(4) receptor is a G-protein coupled receptor with little homology to the pro-inflammatory histamine H(1) receptor, expressed on cells of the immune system with hematopoietic lineage such as eosinophils and mast cells. The effects of the recently described highly selective histamine H(4) receptor antagonists JNJ 10191584 and JNJ 7777120 have now been investigated on the acute colitis provoked by trinitrobenzene sulphonic acid over 3 days in the rat. Treatment with JNJ 10191584 (10-100 mg/kg p.o., b.i.d.) caused a dose-dependent reduction in macroscopic damage, inhibition of the TNBS-provoked elevation of both colonic myeloperoxidase and tumour necrosis factor-alpha (TNF-alpha), and a reduction in the histologically assessed increase in mucosal and submucosal thickness and neutrophil infiltration. JNJ 7777120 (100 mg/kg p.o., b.i.d.) likewise reduced the macroscopic injury and the increases in colonic myeloperoxidase and TNF-alpha levels. These findings indicate a pro-inflammatory role for the histamine H(4) receptor in this model and suggest a novel pharmacological approach to the treatment of colitis.
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http://dx.doi.org/10.1016/j.ejphar.2005.08.045DOI Listing
October 2005

A potent and selective histamine H4 receptor antagonist with anti-inflammatory properties.

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

Johnson & Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.

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.
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http://dx.doi.org/10.1124/jpet.103.061754DOI Listing
April 2004
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