RT Journal Article
SR Electronic
T1 Antipruritic Effect of the Topical Phosphodiesterase 4 Inhibitor E6005 Ameliorates Skin Lesions in a Mouse Atopic Dermatitis Model
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 105
OP 112
DO 10.1124/jpet.113.205542
VO 346
IS 1
A1 Ishii, Naoto
A1 Shirato, Manabu
A1 Wakita, Hisashi
A1 Miyazaki, Kazuki
A1 Takase, Yasutaka
A1 Asano, Osamu
A1 Kusano, Kazutomi
A1 Yamamoto, Eiichi
A1 Inoue, Chiharu
A1 Hishinuma, Ieharu
YR 2013
UL http://jpet.aspetjournals.org/content/346/1/105.abstract
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.