Oral chymase inhibitor SUN13834 ameliorates skin inflammation as well as pruritus in mouse model for atopic dermatitis

Terakawa, Maki; Fujieda, Yusuke; Tomimori, Yoshiaki; Muto, Tsuyoshi; Tanaka, Taisaku; Maruoka, Hiroshi; Nagahira, Kazuhiro; Ogata, Atsuto; Nakatsuka, Takashi; Fukuda, Yoshiaki

doi:10.1016/j.ejphar.2008.10.040

Cited by 27 publications

(16 citation statements)

References 31 publications

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“…Of particular note is the use of reagents specifically targeting mast cells. For example, the use of a mast cell chymase inhibitor in the NC/Nga model showed mast cell chymase may be involved in itch induction [104]. This chymase inhibitor reduced clinical score and mast cell counts in the involved skin [105].…”

Section: The Role Of Mast Cells In Mouse Models Of Admentioning

confidence: 99%

IgE, Mast Cells, and Eosinophils in Atopic Dermatitis

Liu

Goodarzi

Chen

2011

Clinic Rev Allerg Immunol

390

307

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Atopic dermatitis (AD) is a chronic inflammatory skin disease with specific immune and inflammatory mechanisms. Atopy is among the major features of the diagnosis criteria for AD but is not an essential feature. Thus, patients diagnosed with AD can be atopic or non-atopic. This review focuses on the role of IgE, mast cells, and eosinophils in the pathogenesis of AD. The known functions of IgE in allergic inflammation suggest that IgE and IgE-mediated mast cell and eosinophil activation contribute to AD, but direct evidence supporting this is scarce. The level of IgE (thus the degree of allergic sensitization) is associated with severity of AD and contributed by abnormality of skin barrier, a key feature of AD. The function of IgE in development of AD is supported by the beneficial effect of anti-IgE therapy in a number of clinical studies. The role of mast cells in AD is suggested by the increase in the mast cell number and mast cell activation in AD lesions and the association between mast cell activation and AD. It is further suggested by their role in mouse models of AD as well as by the effect of therapeutic agents for AD that can affect mast cells. The role of eosinophils in AD is suggested by the presence of eosinophilia in AD patients and eosinophil infiltrates in AD lesions. It is further supported by information that links AD to cytokines and chemokines associated with production, recruitment, and activation of eosinophils.

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Section: The Role Of Mast Cells In Mouse Models Of Admentioning

confidence: 99%

IgE, Mast Cells, and Eosinophils in Atopic Dermatitis

Liu

Goodarzi

Chen

2011

Clinic Rev Allerg Immunol

390

307

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“…The intake of n-3 longchain polyunsaturated fatty acids as well as ruminant fatty acids exerts protective effects on the development of AD in infants (109). Although the use of protease inhibitor provided promising results in an animal model (110), the first study evaluating the effect of a protease inhibitor in human failed to show an effect in AD (111). Interestingly, besides their immunosuppressive effects, topical corticosteroids and calcineurin inhibitors were shown to normalize epidermal differentiation and expression of filaggrin and loricine in AD skin (112,113).…”

Section: Translating Research Into Therapy For Admentioning

confidence: 99%

Update in clinical allergy and immunology

Gunten

Marsland

Garnier

et al. 2012

Allergy

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In the recent years, a tremendous body of studies has addressed a broad variety of distinct topics in clinical allergy and immunology. In this update, we discuss selected recent data that provide clinically and pathogenetically relevant insights or identify potential novel targets and strategies for therapy. The role of the microbiome in shaping allergic immune responses and molecular, as well as cellular mechanisms of disease, is discussed separately and in the context of atopic dermatitis, as an allergic model disease. Besides summarizing novel evidence, this update highlights current areas of uncertainties and debates that, as we hope, shall stimulate scientific discussions and research activities in the field.Research progress goes ahead fast, and each issue of Allergy distributes a dozen of new and interesting papers providing actual research results, opinions and reviews in different fields of allergy and clinical immunology. Over time, it becomes difficult to keep an overview on the novelties and trends given by these articles. Here, we give an update aiming to summarize interesting papers published in Allergy over the last years and putting them in context with recently published work in the field. As we were not able to cover all fields, we selected three research subjects: (i) Hygiene hypothesis: the role of the microbiome in allergy; (ii) Pathogenic mechanisms of allergic diseases and their potential therapeutic implications; (iii) Atopic dermatitis (AD): skin barrier and allergic inflammation. In our view, the selected papers provide new insights in clinically and pathogenetically important research as well as novel targets and strategies for therapy that might become starting points for future research.

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“…A potent, selective, orally administered chymase inhibitor, SUN13834, is under clinical development for the treatment of atopic dermatitis (AD) (Terakawa et al, 2008). Chymase is a chymotrypsin-like serine protease stored in mast cell granules and is secreted upon cell stimulation (Beghdadi et al, 2011;Welle, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, these compounds reduce scratching behavior induced by repeated percutaneous administration of 2,4-dinitrofluorobenzene in dermatitis models (Terakawa et al, 2008). The physiological mechanisms of chymase inhibitor action for improving AD may include inhibition of inflammatory cell recruitment and activation of stem cell factors (Watanabe et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

In vitroandin vivometabolism of a novel chymase inhibitor, SUN13834, and the predictability of human metabolism using mice with humanized liver

Igawa¹,

Fujitani²,

Shah³

et al. 2013

Xenobiotica

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1. A novel oral chymase inhibitor, SUN13834, is under clinical development for the treatment of atopic dermatitis (AD). In this study, in vitro and in vivo metabolic profiles of SUN13834 were compared between severe combined immunodeficiency (SCID) mice, chimeric mice with humanized liver and humans. 2. In in vitro experiments using liver microsomes, predominant metabolites of SUN13834 were glucuronide (MG-1) in SCID mice and hydroxylated metabolite (M-3) in chimeric mice and humans. 3. After a single oral dose of [(14)C]SUN13834 to SCID and chimeric mice, glucuronidation was the major metabolic pathway in SCID mice, while the parent compound, ring opening form (M-5), O-demethylated form of M-5 (M-6) and glucuronidation of M-6 (M-6G) were detected at higher levels in chimeric mice compared to SCID mice. 4. When AD patients were orally treated using SUN13834 for 28 days, the parent compound had the highest concentration in plasma, and M-6, M-6G, M-5 and MG-1 were identified as major metabolites. 5. This is the first report of SUN13834 metabolic information in human. In addition, based on similarities in metabolic profiles between chimeric mice and humans, it was concluded that chimeric mice are useful for predicting SUN13834 metabolism in humans during early stages of drug development.

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Oral chymase inhibitor SUN13834 ameliorates skin inflammation as well as pruritus in mouse model for atopic dermatitis

Cited by 27 publications

References 31 publications

IgE, Mast Cells, and Eosinophils in Atopic Dermatitis

IgE, Mast Cells, and Eosinophils in Atopic Dermatitis

Update in clinical allergy and immunology

In vitroandin vivometabolism of a novel chymase inhibitor, SUN13834, and the predictability of human metabolism using mice with humanized liver

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