Publications by authors named "Robin L Thurmond"

79 Publications

Preclinical and clinical characterization of the RORγt inhibitor JNJ-61803534.

Sci Rep 2021 May 26;11(1):11066. Epub 2021 May 26.

Janssen Research & Development, LLC, La Jolla, CA, USA.

The nuclear receptor retinoid-related orphan receptor gamma t (RORγt) plays a critical role in driving Th17 cell differentiation and expansion, as well as IL-17 production in innate and adaptive immune cells. The IL-23/IL-17 axis is implicated in several autoimmune and inflammatory diseases, and biologics targeting IL-23 and IL-17 have shown significant clinical efficacy in treating psoriasis and psoriatic arthritis. JNJ-61803534 is a potent RORγt inverse agonist, selectively inhibiting RORγt-driven transcription versus closely-related family members, RORα and RORβ. JNJ-61803534 inhibited IL-17A production in human CD4 T cells under Th17 differentiation conditions, but did not inhibit IFNγ production under Th1 differentiation conditions, and had no impact on in vitro differentiation of regulatory T cells (Treg), nor on the suppressive activity of natural Tregs. In the mouse collagen-induced arthritis model, JNJ-61803534 dose-dependently attenuated inflammation, achieving ~ 90% maximum inhibition of clinical score. JNJ-61803534 significantly inhibited disease score in the imiquimod-induced mouse skin inflammation model, and dose-dependently inhibited the expression of RORγt-regulated genes, including IL-17A, IL-17F, IL-22 and IL-23R. Preclinical 1-month toxicity studies in rats and dogs identified doses that were well tolerated supporting progression into first-in-human studies. An oral formulation of JNJ-61803534 was studied in a phase 1 randomized double-blind study in healthy human volunteers to assess safety, pharmacokinetics, and pharmacodynamics. The compound was well tolerated in single ascending doses (SAD) up to 200 mg, and exhibited dose-dependent increases in exposure upon oral dosing, with a plasma half-life of 164 to 170 h. In addition, dose-dependent inhibition of ex vivo stimulated IL-17A production in whole blood was observed, demonstrating in vivo target engagement. In conclusion, JNJ-61803534 is a potent and selective RORγt inhibitor that exhibited acceptable preclinical safety and efficacy, as well as an acceptable safety profile in a healthy volunteer SAD study, with clear evidence of a pharmacodynamic effect in humans.
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http://dx.doi.org/10.1038/s41598-021-90497-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155022PMC
May 2021

Selective inhibition of peripheral cathepsin S reverses tactile allodynia following peripheral nerve injury in mouse.

Eur J Pharmacol 2020 Aug 11;880:173171. Epub 2020 May 11.

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

Cathepsin S (CatS) is a cysteine protease found in lysosomes of hematopoietic and microglial cells and in secreted form in the extracellular space. While CatS has been shown to contribute significantly to neuropathic pain, the precise mechanisms remain unclear. In this report, we describe JNJ-39641160, a novel non-covalent, potent, selective and orally-available CatS inhibitor that is peripherally restricted (non-CNS penetrant) and may represent an innovative class of immunosuppressive and analgesic compounds and tools useful toward investigating peripheral mechanisms of CatS in neuropathic pain. In C57BL/6 mice, JNJ-39641160 dose-dependently blocked the proteolysis of the invariant chain, and inhibited both T-cell activation and antibody production to a vaccine antigen. In the spared nerve injury (SNI) model of chronic neuropathic pain, in which T-cell activation has previously been demonstrated to be a prerequisite for the development of pain hypersensitivity, JNJ-39641160 fully reversed tactile allodynia in wild-type mice but was completely ineffective in the same model in CatS knockout mice (which exhibited a delayed onset in allodynia). By contrast, in the acute mild thermal injury (MTI) model, JNJ-39641160 only weakly attenuated allodynia at the highest dose tested. These findings support the hypothesis that blockade of peripheral CatS alone is sufficient to fully reverse allodynia following peripheral nerve injury and suggest that the mechanism of action likely involves interruption of T-cell activation and peripheral cytokine release. In addition, they provide important insights toward the development of selective CatS inhibitors for the treatment of neuropathic pain in humans.
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http://dx.doi.org/10.1016/j.ejphar.2020.173171DOI Listing
August 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

Efficacy and Safety of Toreforant, a Selective Histamine H4 Receptor Antagonist, for the Treatment of Moderate-to-Severe Plaque Psoriasis: Results from a Phase 2 Multicenter, Randomized, Double-blind, Placebo-controlled Trial.

J Drugs Dermatol 2018 Aug;17(8):873-879

Background: Toreforant is a selective histamine H4 receptor antagonist. H4 receptor activation may play a role in immune-mediated inflammation in psoriasis.

Objective: To evaluate Toreforant efficacy and safety in patients with moderate-to-severe psoriasis.

Methods: Biologic-naïve patients were to be treated (30, 60, or 3 mg Toreforant or placebo) for 12 weeks and followed through week 16. In this adaptive-design study, assignments were guided by interim analyses. Primary and major secondary efficacy endpoints, evaluated using Bayesian analyses, were the proportions of patients achieving ≥75% improvement in Psoriasis Area and Severity Index (PASI) from baseline and achieving Investigator's Global Assessment (IGA) of cleared (0) or minimal (1), respectively, at week 12.

Results: Per interim analyses results, patients were randomized to 30 (n = 30) or 60 mg (n = 26) Toreforant or placebo (n = 6). The estimated mean difference in the PASI 75 response rate at week 12 from the posterior distributions compared to placebo was 14.1% (95% credible interval [CI], -0.1% to 30.9%) and 8.9% (95% CI, -5.0% to 24.3%) with 30 and 60 mg Toreforant, respectively. The posterior probabilities of 30 and 60 mg Toreforant inducing a greater response rate than placebo were 97.4% and 90.3%, respectively; neither met the 97.5% predefined success criterion. Results for the IGA 0/1 endpoint were similar. Toreforant was generally safe and well tolerated. No deaths, serious or opportunistic infections, active tuberculosis, or malignancies were reported.

Conclusions: Toreforant efficacy at 30 and 60 mg was greater than placebo but did not meet predefined success criterion. J Drugs Dermatol. 2018;17(8):873-879.
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August 2018

A phase 2a study of toreforant, a histamine H receptor antagonist, in eosinophilic asthma.

Ann Allergy Asthma Immunol 2018 11 11;121(5):568-574. Epub 2018 Aug 11.

Janssen Research & Development, LLC, San Diego, California.

Background: Data from preclinical and clinical studies support the evaluation of histamine 4 receptor antagonists in the treatment of asthma. Toreforant is a selective histamine 4 receptor antagonist that could be effective in patients with eosinophilic asthma.

Objective: To evaluate the efficacy and safety of toreforant in patients with eosinophilic, persistent asthma that was inadequately controlled despite current treatment.

Methods: In this phase 2a, multicenter, randomized, double-blinded, parallel-group, placebo-controlled, proof-of-concept study, 162 eligible patients were randomized (1:1) to placebo or 30 mg of toreforant once daily through week 24 and followed for 4 weeks. The primary end point was change from baseline in pre-bronchodilator percent-predicted forced expiratory volume in 1 second at week 16. Secondary end points included change from baseline at week 16 in postbronchodilator percent-predicted forced expiratory volume in 1 second, Asthma Control Questionnaire scores, weekly averages of Daytime and Nighttime Asthma Diary Symptom Scores, and weekly average of number of puffs in a day that rescue medication was used.

Results: There was no significant difference between groups in pre-bronchodilator percent-predicted forced expiratory volume in 1 second at week 16 (difference in least-square means -0.19%; 95% confidence interval -3.01 to 2.64; P = .90). Similarly, there were no significant differences between groups at week 16 in changes from baseline in the secondary end points (P ≥ .30). Toreforant was generally well tolerated. No deaths or serious adverse events were reported at any time point.

Conclusion: Toreforant, at the dose tested, failed to provide therapeutic benefit in this population of patients with uncontrolled, eosinophilic, persistent asthma.

Trial Registration: ClinicalTrials.gov, NCT01823016.
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http://dx.doi.org/10.1016/j.anai.2018.08.001DOI Listing
November 2018

Histamine H receptor antagonism prevents the progression of diabetic nephropathy in male DBA2/J mice.

Pharmacol Res 2018 02 6;128:18-28. Epub 2018 Jan 6.

Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125, Turin, Italy. Electronic address:

Due to the incidence of diabetes and the related morbidity of diabetic nephropathy, identification of new therapeutic strategies represents a priority. In the last few decades new and growing evidence on the possible role of histamine in diabetes has been provided. In particular, the histamine receptor HR is emerging as a new promising pharmacological target for diabetic nephropathy. The aim of this study was to evaluate the efficacy of selective HR antagonism by JNJ39758979 on the prevention of diabetic nephropathy progression in a murine model of diabetes induced by streptozotocin injection. JNJ39758979 (25, 50, 100 mg/kg/day p.o.) was administered for 15 weeks starting from the onset of diabetes. Functional parameters were monitored throughout the experimental period. JNJ39758979 did not significantly affect glycaemic status or body weight. The urine analysis indicated a dose-dependent inhibitory effect of JNJ39758979 on Albumin-Creatinine-Ratio, the Creatinine Clearance, the 24 h urine volume, and pH urine acidification (P < 0.05). The beneficial effects of JNJ39758979 on renal function paralleled comparable effects on renal morphological integrity. These effects were sustained by a significant immune infiltration and fibrosis reduction. Notably, megalin and sodium-hydrogen-exchanger 3 expression levels were preserved. Our data suggest that the HR participates in diabetic nephropathy progression through both a direct effect on tubular reabsorption and an indirect action on renal tissue architecture via inflammatory cell recruitment. Therefore, HR antagonism emerges as a possible new multi-mechanism therapeutic approach to counteract development of diabetic nephropathy development.
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http://dx.doi.org/10.1016/j.phrs.2018.01.002DOI Listing
February 2018

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

Behavioural phenotype of histamine H receptor knockout mice: Focus on central neuronal functions.

Neuropharmacology 2017 03 27;114:48-57. Epub 2016 Nov 27.

Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy. Electronic address:

The functional expression of H receptors (HR) within neurons of the central nervous system has been recently reported, but their role is poorly understood. The present study aims to elucidate the role of neuronal HR by providing the first description of the behavioural phenotype of HR-deficient (HR knockout, HR-KO) mice. Mice lacking HR underwent behavioural studies to evaluate locomotor activity, pain perception, anxiety, depression, memory and feeding behaviour. HR-KO mice showed a significant increase in ambulation in an open field as well as in exploratory activity in the absence of any modification of motor coordination. The sensitivity of mutant mice to a thermal or a mechanical stimulus was identical to that of the wild type mice, but HR-KO showed sensory hypersensitivity toward a condition of neuropathic pain. The lack of HR is associated with the promotion of anxiety in the light-dark box test. HR-KO mice showed an increased immobility time in the tail suspension test, experimental procedure used to evaluate the response of HR deficient mice to a behavioural despair paradigm. Cognitive function parameters of HR deficient mice, examined using the passive avoidance and the novel object recognition tests, were unaltered showing the lack of influence of HR on working and recognition memory. Finally, HR-deficient mice showed an orectic phenotype. These results illustrate that HR modulates various neurophysiological functions such as locomotor activity, anxiety, nociception and feeding behaviour, confirming the importance of the integrity and functionality of neuronal HR in the histaminergic regulation of neuronal functions.
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http://dx.doi.org/10.1016/j.neuropharm.2016.11.023DOI Listing
March 2017

Toreforant, A Histamine H4 Receptor Antagonist, in Patients with Active Rheumatoid Arthritis Despite Methotrexate Therapy: Results of 2 Phase II Studies.

J Rheumatol 2016 09 15;43(9):1637-42. Epub 2016 Jul 15.

From the Immunology department, Janssen Research & Development, LLC, San Diego, California; the Medical Affairs department, Janssen Research & Development, LLC, Horsham, Pennsylvania; the Biostatistics department and the Immunology department, Janssen Research & Development, LLC, Spring House, Pennsylvania, USA; Early Development, Janssen China Research and Development, Shanghai, China; the Biostatistics department, Janssen Research & Development, LLC, Belmont, Massachusetts, USA; Rheumatology Department, M&M Centers LTD., Adazi, Latvia; Immunology Department, University of Rochester, Rochester, New York, USA; Internal Medicine, University of Occupational and Environmental Health, Kitakyushu; Rheumatology, Keio University Hospital, Tokyo, Japan; Rheumatology, Medical University of Vienna and Hietzing Hospital, Vienna, Austria.R.L. Thurmond, PhD, Immunology Department, Janssen Research & Development, LLC; A. Greenspan, MD, Medical Affairs Department, Janssen Research & Development, LLC; W. Radziszewski, MD, PhD, Immunology Department, Janssen Research & Development, LLC; X.L. Xu, PhD, Immunology Department, Janssen Research & Development, LLC; Y. Miao, MS, Biostatistics Department, Janssen Research & Development, LLC; B. Chen, PhD, Early Development, Janssen China Research and Development; T. Ge, PhD, Biostatistics Department, Janssen Research & Development, LLC; B. Zhou, PhD, Biostatistics, Janssen Research & Development, LLC; D.G. Baker, MD, Immunology Department, Janssen Research & Development, LLC; D. Pavlova, MD, Rheumatology, M&M Centers Ltd.; C.T. Ritchlin, MD, Immunology Department, University of Rochester; Y. Tanaka, MD, PhD, Internal Medicine, University of Occupational and Environmental Health; T. Takeuchi, MD, PhD, Rheumatology, Keio University Hospital; J.S. Smolen, MD, Rheumatology, Medical University of Vienna and Hietzing Hospital.

Objective: To assess toreforant (selective histamine H4 receptor antagonist) in active rheumatoid arthritis (RA).

Methods: In a phase IIa, double-blind, placebo-controlled test, 86 patients were randomized (2:1) to once-daily toreforant 100 mg or placebo for 12 weeks. In phase IIb, double-blind, placebo-controlled, dose-range-finding evaluations, 272 patients were randomized (1:1:1:1) to once-daily placebo or toreforant 3/10/30 mg. Primary efficacy endpoints for both studies were Week 12 changes in 28-joint Disease Activity Score-C-reactive protein (DAS28-CRP).

Results: Phase IIa testing was terminated prematurely (patient fatality; secondary hemophagocytic lymphohistiocytosis). Posthoc analyses indicated toreforant 100 mg/day reduced RA signs/symptoms through Week 12. Phase IIb testing, however, showed no significant Week 12 improvement in DAS28-CRP with toreforant.

Conclusion: Toreforant was not effective in phase IIb testing.
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http://dx.doi.org/10.3899/jrheum.160164DOI Listing
September 2016

Results from a Phase IIA Parallel Group Study of JNJ-40346527, an Oral CSF-1R Inhibitor, in Patients with Active Rheumatoid Arthritis despite Disease-modifying Antirheumatic Drug Therapy.

J Rheumatol 2015 Oct 1;42(10):1752-60. Epub 2015 Aug 1.

From the Division of Rheumatology, Stanford University, Palo Alto; Immunology, and Biostatistics, Janssen Research and Development LLC, La Jolla, California; Immunology, Janssen Research and Development, LLC, Spring House; Medical Affairs, Janssen Scientific Affairs LLC, Horsham, Pennsylvania; Quantitative Sciences, Janssen Research and Development LLC, Titusville, New Jersey, USA.M.C. Genovese, MD, Division of Rheumatology, Stanford University; E. Hsia, MD; S.M. Belkowski, PhD, Immunology, Janssen Research and Development LLC; C. Chien, PhD, Quantitative Sciences, Janssen Research and Development LLC; T. Masterson, MS; R.L. Thurmond, PhD; C.L. Manthey, PhD, Immunology, Janssen Research and Development LLC; X. Yan, PhD, Quantitative Sciences, Janssen Research and Development LLC; T. Ge, PhD, Biostatistics, Janssen Research and Development LLC; C. Franks, BS, Immunology, Janssen Research and Development LLC; A. Greenspan, MD, Medical Affairs, Janssen Scientific Affairs LLC.

Objective: To assess the efficacy and safety of JNJ-40346527, a selective inhibitor of colony-stimulating factor-1 (CSF-1) receptor kinase that acts to inhibit macrophage survival, proliferation, and differentiation in patients with active rheumatoid arthritis (RA) despite disease-modifying antirheumatic drug (DMARD) therapy.

Methods: In this randomized, double-blind, placebo-controlled, parallel group study, adults were randomized (2:1) to receive oral JNJ-40346527 100 mg or placebo twice daily through Week 12. Patients with RA had disease activity [≥ 6 swollen/≥ 6 tender joints, C-reactive protein (CRP) ≥ 0.8 mg/dl] despite DMARD therapy for ≥ 6 months. The primary endpoint was change from baseline at Week 12 in the 28-joint Disease Activity Score with CRP (DAS28-CRP). Pharmacokinetic/pharmacodynamic analyses were also performed, and safety was assessed through Week 16.

Results: Ninety-five patients were treated (63 JNJ-40346527, 32 placebo); 8 patients discontinued treatment (6 JNJ-40346527, 2 placebo) through Week 12. Mean improvements in DAS28-CRP from baseline to Week 12 were 1.15 for the JNJ-40346527 group and 1.42 for the placebo group (p = 0.30); thus, a statistically significant difference was not observed for the primary endpoint. Pharmacokinetic exposure to JNJ-40346527 and its active metabolites was above the projected concentration needed for pharmacologic activity, and effective target engagement and proof of activity were demonstrated by increased levels of CSF-1 and decreased CD16+ monocytes in JNJ-40346527-treated, but not placebo-treated, patients. Thirty-seven (58.7%) JNJ-40346527-treated and 16 (50.0%) placebo-treated patients reported ≥ 1 adverse event (AE); 1 (1.6%) JNJ-40346527-treated and 3 (9.4%) placebo-treated patients reported ≥ 1 serious AE.

Conclusion: Although adequate exposure and effective peripheral target engagement were evident, JNJ-40346527 efficacy was not observed in patients with DMARD-refractory active RA. ClinicalTrials.gov identifier: NCT01597739. EudraCT Number: 2011-004529-28.
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http://dx.doi.org/10.3899/jrheum.141580DOI Listing
October 2015

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors.

Pharmacol Rev 2015 Jul;67(3):601-55

Department of Anatomy, and Neuroscience Center, University of Helsinki, Finland (P.P.); School of Biological and Biomedical Sciences, University of Durham, United Kingdom (P.L.C.); AbbVie, Inc. North Chicago, Illinois (M.C.); Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany (R.G.); Department of Medicinal Chemistry, Amsterdam Institute of Molecules, Medicines and Systems, VU University Amsterdam, The Netherlands (R.L.); Ziarco Pharma Limited, Canterbury, United Kingdom (W.L.S.L.); Institute of Pharmaceutical and Medical Chemistry and Institute of Neurophysiology, Medical Faculty, Westfalische-Wilhelms-University, Muenster, Germany (H.L.H.); Heinrich-Heine-University Duesseldorf, Germany (H.S.); and Janssen Research & Development, LLC, San Diego, California (R.L.T.).

Histamine is a developmentally highly conserved autacoid found in most vertebrate tissues. Its physiological functions are mediated by four 7-transmembrane G protein-coupled receptors (H1R, H2R, H3R, H4R) that are all targets of pharmacological intervention. The receptors display molecular heterogeneity and constitutive activity. H1R antagonists are long known antiallergic and sedating drugs, whereas the H2R was identified in the 1970s and led to the development of H2R-antagonists that revolutionized stomach ulcer treatment. The crystal structure of ligand-bound H1R has rendered it possible to design new ligands with novel properties. The H3R is an autoreceptor and heteroreceptor providing negative feedback on histaminergic and inhibition on other neurons. A block of these actions promotes waking. The H4R occurs on immuncompetent cells and the development of anti-inflammatory drugs is anticipated.
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http://dx.doi.org/10.1124/pr.114.010249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485016PMC
July 2015

Functional Profiling of 2-Aminopyrimidine Histamine H4 Receptor Modulators.

J Med Chem 2015 Sep 3;58(18):7119-27. Epub 2015 Jun 3.

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

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.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00516DOI Listing
September 2015

The histamine H4 receptor: from orphan to the clinic.

Authors:
Robin L Thurmond

Front Pharmacol 2015 31;6:65. Epub 2015 Mar 31.

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

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.
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http://dx.doi.org/10.3389/fphar.2015.00065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4379874PMC
April 2015

Antihistamines and itch.

Handb Exp Pharmacol 2015 ;226:257-90

Janssen Research and Development, L.L.C., San Diego, CA, 92121, USA,

Histamine is one of the best-characterized pruritogens in humans. It is known to play a role in pruritus associated with urticaria as well as ocular and nasal allergic reactions. Histamine mediates its effect via four receptors. Antihistamines that block the activation of the histamine H₁receptor, H₁R, have been shown to be effective therapeutics for the treatment of pruritus associated with urticaria, allergic rhinitis, and allergic conjunctivitis. However, their efficacy in other pruritic diseases such as atopic dermatitis and psoriasis is limited. The other histamine receptors may also play a role in pruritus, with the exception of the histamine H₂receptor, H₂R. Preclinical evidence indicates that local antagonism of the histamine H₃receptor, H₃R, can induce scratching perhaps via blocking inhibitory neuronal signals. The histamine H₄receptor, H₄R, has received a significant amount of attention as to its role in mediating pruritic signals. Indeed, it has now been shown that a selective H₄R antagonist can inhibit histamine-induced itch in humans. This clinical result, in conjunction with efficacy in various preclinical pruritus models, points to the therapeutic potential of H₄R antagonists for the treatment of pruritus not controlled by antihistamines that target the H₁R.
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http://dx.doi.org/10.1007/978-3-662-44605-8_15DOI Listing
July 2015

Diaminopyrimidines, diaminopyridines and diaminopyridazines as histamine H4 receptor modulators.

Bioorg Med Chem Lett 2015 Feb 23;25(4):956-9. Epub 2014 Dec 23.

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

Previously disclosed H4 receptor modulators, the triamino substituted pyridines and pyrimidines, contain a free primary amino (-NH2) group. In this Letter we demonstrate that an exocyclic amine (NH2) is not needed to maintain affinity, and also show a significant divergence in the SAR of the pendant diamine component. These des-NH2 azacycles also show a distinct functional spectrum, that appears to be influenced by the diamine component; in the case of the 1,3-amino pyrimidines, the preferred diamine is the amino pyrrolidine instead of the more common piperazines. Finally, we introduce 3,5-diamino pyridazines as novel histamine H4 antagonists.
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http://dx.doi.org/10.1016/j.bmcl.2014.12.027DOI Listing
February 2015

Phase 2a, randomized, double-blind, placebo-controlled, multicenter, parallel-group study of a H4 R-antagonist (JNJ-39758979) in Japanese adults with moderate atopic dermatitis.

J Dermatol 2015 Feb 9;42(2):129-39. Epub 2014 Dec 9.

Research & Development, Janssen Pharmaceutical KK, Tokyo, Japan.

This trial was conducted to evaluate the safety and efficacy of the H4 R-antagonist JNJ-39758979 in adult Japanese patients with moderate atopic dermatitis (AD). Eligible patients were randomly assigned to JNJ-39758979 300 mg, 100 mg or placebo once daily for 6 weeks in this phase 2a, double-blind, multicenter, placebo-controlled study. Primary efficacy was assessed via week-6 Eczema Area and Severity Index (EASI) scores. Secondary efficacy assessments included Investigator's Global Assessment (IGA) and patient-reported outcome (PRO) pruritus assessments (Pruritus Categorical Response Scale [PCRS], Pruritus Numeric Rating Scales [PNRS], Pruritus Interference Numeric Rating Scale [PINRS] and Subject's Global Impressions of Change in Pruritus [SGICP]). Eighty-eight of 105 planned patients were randomized before the study was stopped and unblinded for safety reasons. The study did not meet the primary end-point. However, numerical improvements (i.e. decreases) in median EASI were observed with JNJ-39758979 100 mg (-3.7) and 300 mg (-3.0) versus placebo (-1.3) at week 6. Nominally significant improvements across PRO PCRS, PNRS and SGICP assessments were consistently observed, particularly with JNJ-39758979 300 mg. Safety, including adverse events (AE), was comparable between JNJ-39758979 and placebo with the exception of two patients (both receiving JNJ-39758979 300 mg) with serious AE of neutropenia, leading to premature study discontinuation. No deaths were reported. Except for neutropenia, no clinically relevant changes in laboratory values were observed. Although not conclusive, findings suggest H4 R-antagonism may be beneficial for AD, particularly in controlling pruritus. JNJ-39758979 appears to be associated with drug-induced agranulocytosis, likely an off-target effect.
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http://dx.doi.org/10.1111/1346-8138.12726DOI Listing
February 2015

The effect of pK(a) on pyrimidine/pyridine-derived histamine H4 ligands.

Bioorg Med Chem Lett 2014 Dec 13;24(23):5489-92. Epub 2014 Oct 13.

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

During the course of our efforts toward the discovery of human histamine H4 antagonists from a series of 2-aminiopyrimidines, it was noted that a 6-trifluoromethyl group dramatically reduced affinity of the series toward the histamine H4 receptor. This observation was further investigated by synthesizing a series of ligands that varied in pKa of the pyrimidine derived H4 ligands by over five orders of magnitude and the effect on histamine H4 affinity. This trend was then extended to the discovery of C-linked piperidinyl-2-amino pyridines as histamine H4 receptor antagonists.
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http://dx.doi.org/10.1016/j.bmcl.2014.10.013DOI Listing
December 2014

Prevention of bleomycin-induced lung inflammation and fibrosis in mice by naproxen and JNJ7777120 treatment.

J Pharmacol Exp Ther 2014 Nov 2;351(2):308-16. Epub 2014 Sep 2.

Departments of Drug Science and Technology, University of Turin, Turin, Italy (A.C.R., E.V.); Department of Neuroscience, Psychiatry, and Drug Research, Section of Pharmacology (L.L., C.L., E.M.), and Experimental and Clinical Medicine (A.P.), University of Florence, Florence, Italy; Janssen Research & Development, L.L.C., San Diego, California (R.L.T.); and Heinrich-Heine Düsseldorf University, Institute of Medicinal Chemistry, Düsseldorf, Germany (H.S.)

Pulmonary fibrosis, a progressive and lethal lung disease characterized by inflammation and accumulation of extracellular matrix components, is a major therapeutic challenge for which new therapeutic strategies are warranted. Cyclooxygenase (COX) inhibitors have been previously utilized to reduce inflammation. Histamine H4 receptor (H4R), largely expressed in hematopoietic cells, has been identified as a novel target for inflammatory and immune disorders. The aim of this study was to evaluate the effect of JNJ7777120 (1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine), a selective H4R antagonist, and naproxen, a well known nonsteroidal anti-inflammatory drug, and their combination in a murine model of bleomycin-induced fibrosis. Bleomycin (0.05 IU) was instilled intratracheally to C57BL/6 mice, which were then treated by micro-osmotic pump with vehicle, JNJ7777120 (40 mg/kg b.wt.), naproxen (21 mg/kg b.wt.), or a combination of both. Airway resistance to inflation, an index of lung stiffness, was assessed, and lung specimens were processed for inflammation, oxidative stress, and fibrosis markers. Both drugs alone were able to reduce the airway resistance to inflation induced by bleomycin and the inflammatory response by decreasing COX-2 and myeloperoxidase expression and activity and thiobarbituric acid-reactive substance and 8-hydroxy-2'-deoxyguanosine production. Lung fibrosis was inhibited, as demonstrated by the reduction of tissue levels of transforming growth factor-β, collagen deposition, relative goblet cell number, and smooth muscle layer thickness. Our results demonstrate that both JNJ7777120 and naproxen exert an anti-inflammatory and antifibrotic effect that is increased by their combination, which could be an effective therapeutic strategy in the treatment of pulmonary fibrosis.
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http://dx.doi.org/10.1124/jpet.114.215152DOI Listing
November 2014

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

The histamine H4 receptor is a potent inhibitor of adhesion-dependent degranulation in human neutrophils.

J Leukoc Biol 2014 Sep 5;96(3):411-8. Epub 2014 May 5.

Centre for Infection and Immunity, Queen's University of Belfast, Northern Ireland, United Kingdom;

The histamine H4 receptor regulates the inflammatory response. However, it is not known whether this receptor has a functional role in human neutrophils. We found that fMLP (1 μM), but not histamine (0.1-1 μM), induced Mac-1-dependent adhesion, polarization, and degranulation (release of lactoferrin). A pretreatment of neutrophils with histamine (0.001-1 μM) or JNJ 28610244 (0.1-10 μM), a specific H4 receptor agonist, led to inhibition of degranulation. Total inhibition of degranulation was obtained with 0.1 μM histamine and 10 μM JNJ 28610244. Furthermore, such inhibition by histamine of degranulation was reversed by JNJ 7777120 and JNJ 28307474, two selective H4 receptor antagonists. However, neither histamine nor the H4 receptor agonist JNJ 28610244 prevented fMLP-induced, Mac-1-dependent adhesion, indicating that the H4 receptor may block signals emanating from Mac-1-controlling degranulation. Likewise, engagement of the H4 receptor by the selective agonist JNJ 28610244 blocked Mac-1-dependent activation of p38 MAPK, the kinase that controls neutrophil degranulation. We also show expression of the H4 receptor at the mRNA level in ultrapure human neutrophils and myeloid leukemia PLB-985 cells. We concluded that engagement of this receptor by selective H4 receptor agonists may represent a good, therapeutic approach to accelerate resolution of inflammation.
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http://dx.doi.org/10.1189/jlb.2AB0813-432RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395935PMC
September 2014

Histamine H4-receptors inhibit mast cell renin release in ischemia/reperfusion via protein kinase C ε-dependent aldehyde dehydrogenase type-2 activation.

J Pharmacol Exp Ther 2014 Jun 2;349(3):508-17. Epub 2014 Apr 2.

Department of Pharmacology, Weill Cornell Medical College, New York, New York, (S.A., K.-i.T., K.T., K.K., N.C., A.M., M.S.-R., R.L.); and Department of Immunology, Janssen Research & Development, L.L.C., San Diego, California (R.L.T.).

Renin released by ischemia/reperfusion (I/R) from cardiac mast cells (MCs) activates a local renin-angiotensin system (RAS) causing arrhythmic dysfunction. Ischemic preconditioning (IPC) inhibits MC renin release and consequent activation of this local RAS. We postulated that MC histamine H4-receptors (H4Rs), being Gαi/o-coupled, might activate a protein kinase C isotype-ε (PKCε)-aldehyde dehydrogenase type-2 (ALDH2) cascade, ultimately eliminating MC-degranulating and renin-releasing effects of aldehydes formed in I/R and associated arrhythmias. We tested this hypothesis in ex vivo hearts, human mastocytoma cells, and bone marrow-derived MCs from wild-type and H4R knockout mice. We found that activation of MC H4Rs mimics the cardioprotective anti-RAS effects of IPC and that protection depends on the sequential activation of PKCε and ALDH2 in MCs, reducing aldehyde-induced MC degranulation and renin release and alleviating reperfusion arrhythmias. These cardioprotective effects are mimicked by selective H4R agonists and disappear when H4Rs are pharmacologically blocked or genetically deleted. Our results uncover a novel cardioprotective pathway in I/R, whereby activation of H4Rs on the MC membrane, possibly by MC-derived histamine, leads sequentially to PKCε and ALDH2 activation, reduction of toxic aldehyde-induced MC renin release, prevention of RAS activation, reduction of norepinephrine release, and ultimately to alleviation of reperfusion arrhythmias. This newly discovered protective pathway suggests that MC H4Rs may represent a new pharmacologic and therapeutic target for the direct alleviation of RAS-induced cardiac dysfunctions, including ischemic heart disease and congestive heart failure.
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http://dx.doi.org/10.1124/jpet.114.214122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019319PMC
June 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

Histamine synthesis is required for granule maturation in murine mast cells.

Eur J Immunol 2014 Jan 1;44(1):204-14. Epub 2013 Oct 1.

Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.

Mast cells are the major sources of histamine, which is released in response to immunological stimulations. The synthesis of histamine is catalyzed by histidine decarboxylase (HDC). Previous studies have shown that Hdc(-/-) mast cells exhibit aberrant granule morphology with severely decreased granule content. Here, we investigated whether the histamine synthesized in mast cells regulates the granule maturation of murine mast cells. Several genes, including those encoding granule proteases and enzymes involved in heparin biosynthesis, were downregulated in Hdc(-/-) peritoneal mast cells. Impaired granule maturation was also found in Hdc(-/-) BM-derived cultured mast cells when they were cocultured with fibroblasts in the presence of c-kit ligand. Exogenous application of histamine and several H4 receptor agonists restored the granule maturation of Hdc(-/-) cultured mast cells. However, the maturation of granules was largely normal in Hrh4(-/-) peritoneal mast cells. Depletion of cellular histamine with tetrabenazine, an inhibitor of vesicular monoamine transporter-2, did not affect granule maturation. In vivo experiments with mast cell deficient Kit(W) /Kit(W-v) mice indicated that the expression of the Hdc gene in mast cells is required for granule maturation. These results suggest that histamine promotes granule maturation in mast cells and acts as an proinflammatory mediator.
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http://dx.doi.org/10.1002/eji.201343838DOI Listing
January 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 down-regulates IL-27 production in antigen-presenting cells.

J Leukoc Biol 2012 Jul 2;92(1):21-9. Epub 2012 Mar 2.

Hannover Medical School, Department of Dermatology and Allergy, Division of Immunodermatology and Allergy Research, Hannover, Germany. [email protected]

Histamine is a potent mediator in allergic inflammation with immunomodulatory properties. Since histamine was described to inhibit IL-12 production in human APCs, we hypothesized that also the expression of IL-27, a newly described member of the IL-12 family, which is present in inflammatory skin lesions, is modulated by histamine. Stimulation of human monocytes with histamine resulted in significant reduction of TLR ligand-induced IL-27 production in human monocytes. IL-27 subunits, p28 and EBI3, were down-regulated at the mRNA and protein level, whereas other cytokines, such as IL-6, IL-10, and TNF-α, were not influenced. Studies with histamine receptor-specific agonists and antagonists showed that the down-regulation of IL-27 was mediated via H(2)R and H(4)R but not H(1)R and H(3)R. Human KCs treated with supernatants of histamine-prestimulated monocytes induced significantly less CXCL10 than supernatants containing high levels of IL-27. DCs from H(4)R(-/-) mice responded to TLR simulation with higher IL-27 production as compared with WT mice. The down-regulation of IL-27 by histamine might be a new mechanism in the pathogenesis of inflammatory skin diseases, in particular, if increased concentrations of histamine are present at sites of inflammation, such as in chronic eczema and psoriasis.
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http://dx.doi.org/10.1189/jlb.0111017DOI Listing
July 2012

Histamine H4 receptor optimizes T regulatory cell frequency and facilitates anti-inflammatory responses within the central nervous system.

J Immunol 2012 Jan 5;188(2):541-7. Epub 2011 Dec 5.

Department of Medicine, Immunobiology Program, University of Vermont, Burlington, VT 05405, USA.

Histamine is a biogenic amine that mediates multiple physiological processes, including immunomodulatory effects in allergic and inflammatory reactions, and also plays a key regulatory role in experimental allergic encephalomyelitis, the autoimmune model of multiple sclerosis. The pleiotropic effects of histamine are mediated by four G protein-coupled receptors, as follows: Hrh1/H(1)R, Hrh2/H(2)R, Hrh3/H(3)R, and Hrh4/H(4)R. H(4)R expression is primarily restricted to hematopoietic cells, and its role in autoimmune inflammatory demyelinating disease of the CNS has not been studied. In this study, we show that, compared with wild-type mice, animals with a disrupted Hrh4 (H(4)RKO) develop more severe myelin oligodendrocyte glycoprotein (MOG)(35\x{2013}55)-induced experimental allergic encephalomyelitis. Mechanistically, we also show that H(4)R plays a role in determining the frequency of T regulatory (T(R)) cells in secondary lymphoid tissues, and regulates T(R) cell chemotaxis and suppressor activity. Moreover, the lack of H(4)R leads to an impairment of an anti-inflammatory response due to fewer T(R) cells in the CNS during the acute phase of the disease and an increase in the proportion of Th17 cells.
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http://dx.doi.org/10.4049/jimmunol.1101498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253209PMC
January 2012

Tricyclic aminopyrimidine histamine H4 receptor antagonists.

Bioorg Med Chem Lett 2011 Nov 19;21(21):6577-81. Epub 2011 Aug 19.

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

This report discloses the development of a series of tricyclic histamine H(4) 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 H(4) receptor antagonist with desirable physiochemical parameters which demonstrated efficacy a mouse ova model.
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http://dx.doi.org/10.1016/j.bmcl.2011.08.014DOI Listing
November 2011