Anti-Pruritic Effect of the Topical Phosphodiesterase 4 Inhibitor E6005

Anti-Pruritic Effect of the Topical Phosphodiesterase 4 Inhibitor E6005 Ameliorates Skin Lesions in a Mouse Atopic Dermatitis Model

1. Naoto Ishii1, 
2. Manabu Shirato1,*, 
3. Hisashi Wakita1, 
4. Kazuki Miyazaki2,
5. Yasutaka Takase1, 
6. Osamu Asano2, 
7. Kazutomi Kusano1,
8. Eiichi Yamamoto1, 
9. Chiharu Inoue2, and 
10. Ieharu Hishinuma2

+Author Affiliations

1. ¹ Eisai Co. Ltd., Tsukuba Research Laboratories, Ibaraki, Japan;
2. ² Eisai Co. Ltd., Tokyo, Japan

1. ↵* Corresponding author; email: m-shirato@hhc.eisai.co.jp

Abstract

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, 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 anti-pruritic effect as well as an anti-inflammatory effect with reduced expression of cytokines/adhesion molecules. Based on 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 anti-pruritic activity for the treatment of AD.

1. Published online before print May 14, 2013, doi:10.1124/jpet.113.205542
   JPET May 14, 2013jpet.113.205542

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