Antipruritic effect of the topical phosphodiesterase 4 inhibitor E6005 ameliorates skin lesions in a mouse atopic dermatitis model
| Autor: | Manabu Shirato, Ieharu Hishinuma, Chiharu Inoue, Naoto Ishii, Kazutomi Kusano, Yasutaka Takase, Eiichi Yamamoto, Kazuki Miyazaki, Hisashi Wakita, Osamu Asano |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Metabolic Clearance Rate Administration Topical Phthalic Acids Inflammation Mice Inbred Strains Pharmacology Monocytes Dermatitis Atopic Rats Sprague-Dawley Mice medicine Distribution (pharmacology) Animals Humans Tissue Distribution Lymphocytes Skin Chemistry Cell adhesion molecule Antipruritic Effect Anti-Inflammatory Agents Non-Steroidal Phosphodiesterase Atopic dermatitis Antipruritics medicine.disease Tacrolimus Cyclic Nucleotide Phosphodiesterases Type 4 Rats Disease Models Animal Quinazolines Molecular Medicine Cytokines Female Phosphodiesterase 4 Inhibitors medicine.symptom Hapten Cell Adhesion Molecules |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 346(1) |
| ISSN: | 1521-0103 |
| Popis: | Phosphodiesterase (PDE) 4 inhibition is a well-known anti-inflammatory mechanism, but the development of PDE4 inhibitors has been hampered by side effects such as nausea and emesis. Local delivery of a PDE4 inhibitor to the site of inflammation may overcome these issues. The purpose of this study was to assess the therapeutic potential of E6005 (methyl 4-[({3-[6,7-dimethoxy-2-(methylamino)quinazolin-4-yl]phenyl}amino)carbonyl]benzoate), a novel PDE4 inhibitor developed as a topical agent for atopic dermatitis (AD). E6005 potently and selectively inhibited human PDE4 activity with an IC₅₀ of 2.8 nM and suppressed the production of various cytokines from human lymphocytes and monocytes with IC₅₀ values ranging from 0.49 to 3.1 nM. In mice models, the topical application of E6005 produced an immediate antipruritic effect as well as an anti-inflammatory effect with reduced expression of cytokines/adhesion molecules. On the basis of these observed effects, topical E6005 ameliorated the appearance of atopic dermatitis-like skin lesions in two types of AD models, hapten- and mite-elicited models, exhibiting inhibitory effects comparable to that of tacrolimus. The use of ¹⁴C-labeled E6005 showed rapid clearance from the blood and low distribution to the brain, contributing to the low emetic potential of this compound. These results suggest that E6005 may be a promising novel therapeutic agent with antipruritic activity for the treatment of AD. |
| Databáze: | OpenAIRE |
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