Development and Application of Chymase Inhibitors: Therapeutic Potential of a Specific Chymase Inhibitor in Atopic Dermatitis
A novel therapeutic mechanism may be the key to improving the chief symptoms and signs of atopic dermatitis (AD), which are persistent pruritus and high serum IgE. We demonstrate here that mast cell chymase may be a possible initiating factor and that the orally active specific inhibitor Y-40613 may...
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Published in | Japanese journal of pharmacology Vol. 90; no. 3; pp. 214 - 217 |
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2002
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Abstract | A novel therapeutic mechanism may be the key to improving the chief symptoms and signs of atopic dermatitis (AD), which are persistent pruritus and high serum IgE. We demonstrate here that mast cell chymase may be a possible initiating factor and that the orally active specific inhibitor Y-40613 may have a therapeutic potential in the treatment of AD. We found that Y-40613 (2-[5-amino-2-(4-fluorophenyl)-1,6-dihydro-6-oxo-1-pyrimidinyl]-N-{1-[(5-methoxycarbonyl-2-benzoxazolyl)carbonyl]-2-phenylethyl}acetamide) dose-dependently suppressed the scratching response in a mouse pruritus model, with inhibitory efficacy enhanced by combination with conventional drugs, suggesting that chymase contributes to the development of pruritus by a unique mechanism or mechanisms. In fact, chymase injected in the model induced the scratching response. In vitro IgE production from mouse B cells was increased by purified rat chymase and suppressed by Y-40613. Increased serum IgE observed in Brown Norway rats injected with mercury chloride was suppressed by Y-40613. Furthermore, Y-40613 lowered ear thickness as well as serum IgE level in a mouse contact dermatitis model. Taken together, these findings suggest that the specific chymase inhibitor Y-40613 may ameliorate symptoms of AD through the dual inhibition of the chymase-dependent IgE production pathway and itching sensation. |
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AbstractList | A novel therapeutic mechanism may be the key to improving the chief symptoms and signs of atopic dermatitis (AD), which are persistent pruritus and high serum IgE. We demonstrate here that mast cell chymase may be a possible initiating factor and that the orally active specific inhibitor Y-40613 may have a therapeutic potential in the treatment of AD. We found that Y-40613 (2-[5-amino-2-(4-fluorophenyl)-1,6-dihydro-6-oxo-1-pyrimidinyl]-N-{1-[(5-methoxycarbonyl-2-benzoxazolyl)carbonyl]-2-phenylethyl}acetamide) dose-dependently suppressed the scratching response in a mouse pruritus model, with inhibitory efficacy enhanced by combination with conventional drugs, suggesting that chymase contributes to the development of pruritus by a unique mechanism or mechanisms. In fact, chymase injected in the model induced the scratching response. In vitro IgE production from mouse B cells was increased by purified rat chymase and suppressed by Y-40613. Increased serum IgE observed in Brown Norway rats injected with mercury chloride was suppressed by Y-40613. Furthermore, Y-40613 lowered ear thickness as well as serum IgE level in a mouse contact dermatitis model. Taken together, these findings suggest that the specific chymase inhibitor Y-40613 may ameliorate symptoms of AD through the dual inhibition of the chymase-dependent IgE production pathway and itching sensation. |
Author | Imada, Teruaki Naito, Koji Yoshikawa, Tsutomu Kobayashi, Fujio Nakamura, Norifumi Komorita, Naruyasu Miyazaki, Mizuo Kondo, Takao |
Author_xml | – sequence: 1 givenname: Teruaki surname: Imada fullname: Imada, Teruaki email: Imada.Teruaki@mf.m-pharma.co.jp organization: Pharmaceuticals Research Division, Mitsubishi Pharma Corporation, Yokohama 227-0033, Japan – sequence: 2 givenname: Naruyasu surname: Komorita fullname: Komorita, Naruyasu organization: Pharmaceuticals Research Division, Mitsubishi Pharma Corporation, Yokohama 227-0033, Japan – sequence: 3 givenname: Fujio surname: Kobayashi fullname: Kobayashi, Fujio organization: Pharmaceuticals Research Division, Mitsubishi Pharma Corporation, Yokohama 227-0033, Japan – sequence: 4 givenname: Koji surname: Naito fullname: Naito, Koji organization: Pharmaceuticals Research Division, Mitsubishi Pharma Corporation, Yokohama 227-0033, Japan – sequence: 5 givenname: Tsutomu surname: Yoshikawa fullname: Yoshikawa, Tsutomu organization: Pharmaceuticals Research Division, Mitsubishi Pharma Corporation, Yokohama 227-0033, Japan – sequence: 6 givenname: Mizuo surname: Miyazaki fullname: Miyazaki, Mizuo organization: Depertment of Pharmacology, Osaka Medical College, Osaka 569-8686, Japan – sequence: 7 givenname: Norifumi surname: Nakamura fullname: Nakamura, Norifumi organization: Pharmaceuticals Research Division, Mitsubishi Pharma Corporation, Yokohama 227-0033, Japan – sequence: 8 givenname: Takao surname: Kondo fullname: Kondo, Takao organization: Pharmaceuticals Research Division, Mitsubishi Pharma Corporation, Yokohama 227-0033, Japan |
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Cites_doi | 10.1093/intimm/9.3.461 10.1016/0014-2999(94)00780-B 10.2332/allergolint.46.117 10.1159/000022782 10.1159/000236348 10.1159/000045326 10.1046/j.1365-2567.2001.01320.x 10.2340/0001555552125128 10.1046/j.1365-2222.1999.00388.x 10.1016/S0140-6736(95)10244-2 10.1084/jem.160.4.1027 10.1016/S0014-2999(98)00343-4 10.1016/S0021-9258(17)32427-4 10.1159/000022815 |
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References_xml | – volume: 9 start-page: 461 year: 1997 ident: 10.1254/jjp.90.214_bib2 article-title: Development of atopic dermatitis-like skin lesion with hyper-production in NC /Nga mice publication-title: Int Immunol doi: 10.1093/intimm/9.3.461 contributor: fullname: Matsuda – volume: 275 start-page: 229 year: 1995 ident: 10.1254/jjp.90.214_bib11 article-title: Scratching behavior induced by pruritogenic but not algesiogenic agents in mice publication-title: Eur J Pharmacol doi: 10.1016/0014-2999(94)00780-B contributor: fullname: Kuraishi – volume: 46 start-page: 117 year: 1997 ident: 10.1254/jjp.90.214_bib12 article-title: Scratching behavior in mice associated with IgE-mediated allergic cutaneous reaction and its pharmacological characterization publication-title: Allergol Intern doi: 10.2332/allergolint.46.117 contributor: fullname: Musoh – volume: 48 start-page: 38 year: 1998 ident: 10.1254/jjp.90.214_bib9 article-title: Association between variants of mast cell chymase gene and serum IgE levels in eczema publication-title: Hum Hered doi: 10.1159/000022782 contributor: fullname: Mao – volume: 72 start-page: 183 year: 1995 ident: 10.1254/jjp.90.214_bib14 article-title: Cyclosporin A exacerbates mercuric chloride-induced vasculitis in the Brown Norway rat publication-title: Lab Invest contributor: fullname: Qasim – volume: 99 start-page: 141 year: 1992 ident: 10.1254/jjp.90.214_bib6 article-title: The effect of mast cell chymase on extracellular matrix: Studies in autoimmune thyroiditis and in cultured thyroid cells publication-title: Int Arch Allergy Immunol doi: 10.1159/000236348 contributor: fullname: Banovac – volume: 81 start-page: 421 year: 1999 ident: 10.1254/jjp.90.214_bib15 article-title: Effect of FK506 in the treatment of autoimmune glomerlonephritis in Brown Norway rats publication-title: Nephron doi: 10.1159/000045326 contributor: fullname: Nakahama – volume: 104 start-page: 333 year: 2001 ident: 10.1254/jjp.90.214_bib16 article-title: Rat mast cell protease-I enhances immunoglobulin E production by mouse B cells stimulated with interleukin-4 publication-title: Immunology doi: 10.1046/j.1365-2567.2001.01320.x contributor: fullname: Yoshikawa – volume: 52 start-page: 125 year: 1972 ident: 10.1254/jjp.90.214_bib3 article-title: Experimental itch in human skin elicited by rat mast cell chymase publication-title: Acta Dermatol doi: 10.2340/0001555552125128 contributor: fullname: Hagermark – volume: 29 start-page: 800 year: 1999 ident: 10.1254/jjp.90.214_bib10 article-title: Association between mast cell chymase genotype and atopic eczema: comparison between patients with atopic eczema alone and those with atopic eczema and atopic respiratory disease publication-title: Clin Exp Allergy doi: 10.1046/j.1365-2222.1999.00388.x contributor: fullname: Tanaka – volume: 348 start-page: 581 year: 1996 ident: 10.1254/jjp.90.214_bib7 article-title: Association between genetic variants of mast cell chymase and eczema publication-title: Lancet doi: 10.1016/S0140-6736(95)10244-2 contributor: fullname: Mao – volume: 160 start-page: 1027 year: 1984 ident: 10.1254/jjp.90.214_bib13 article-title: Degradation of the epidermal-dermal junction by proteolytic enzymes from human skin and human polymorphonuclear leukocytes publication-title: J Exp Med doi: 10.1084/jem.160.4.1027 contributor: fullname: Briggaman – volume: 352 start-page: 91 year: 1998 ident: 10.1254/jjp.90.214_bib4 article-title: The induction of a prolonged increase in microvascular permeability by human mast cell chymase publication-title: Eur J Pharmacol doi: 10.1016/S0014-2999(98)00343-4 contributor: fullname: He – start-page: 22 year: 1995 ident: 10.1254/jjp.90.214_bib1 article-title: Role of mast cells and basophils in asthma contributor: fullname: Redington – volume: 269 start-page: 18134 year: 1994 ident: 10.1254/jjp.90.214_bib5 article-title: Activation of human interstitial procollagenase through direct cleavage of the Leu-Thr bond by mast cell chymase publication-title: J Biol Chem doi: 10.1016/S0021-9258(17)32427-4 contributor: fullname: Saarinen – volume: 48 start-page: 271 year: 1998 ident: 10.1254/jjp.90.214_bib8 article-title: No evidence for an association between a variant of the mast cell chymase gene and atopic dermatitis based on case-control and haplotype-relative-risk analyses publication-title: Hum Hered doi: 10.1159/000022815 contributor: fullname: Kawashima |
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Title | Development and Application of Chymase Inhibitors: Therapeutic Potential of a Specific Chymase Inhibitor in Atopic Dermatitis |
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