PT  - JOURNAL ARTICLE
AU  - Ishii, Naoto
AU  - Shirato, Manabu
AU  - Wakita, Hisashi
AU  - Miyazaki, Kazuki
AU  - Takase, Yasutaka
AU  - Asano, Osamu
AU  - Kusano, Kazutomi
AU  - Yamamoto, Eiichi
AU  - Inoue, Chiharu
AU  - Hishinuma, Ieharu
TI  - Antipruritic Effect of the Topical Phosphodiesterase 4 Inhibitor E6005 Ameliorates Skin Lesions in a Mouse Atopic Dermatitis Model
AID  - 10.1124/jpet.113.205542
DP  - 2013 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 105--112
VI  - 346
IP  - 1
4099  - http://jpet.aspetjournals.org/content/346/1/105.short
4100  - http://jpet.aspetjournals.org/content/346/1/105.full
SO  - J Pharmacol Exp Ther2013 Jul 01; 346
AB  - 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.