title: Antipruritic effect of the topical phosphodiesterase 4 inhibitor E6005 ameliorates skin lesions in a mouse atopic dermatitis model.
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 (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.
authors.affiliation: Eisai Co. Ltd., Tsukuba Research Laboratories, Ibaraki, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Ishii
authors.forename: Manabu
authors.initials: M
authors.lastname: Shirato
authors.forename: Hisashi
authors.initials: H
authors.lastname: Wakita
authors.forename: Kazuki
authors.initials: K
authors.lastname: Miyazaki
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Takase
authors.forename: Osamu
authors.initials: O
authors.lastname: Asano
authors.forename: Kazutomi
authors.initials: K
authors.lastname: Kusano
authors.forename: Eiichi
authors.initials: E
authors.lastname: Yamamoto
authors.forename: Chiharu
authors.initials: C
authors.lastname: Inoue
authors.forename: Ieharu
authors.initials: I
authors.lastname: Hishinuma
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000982:Antipruritics / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008815:Mice, Inbred Strains; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D010795:Phthalic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000982:Antipruritics; D015815:Cell Adhesion Molecules; D016207:Cytokines; D058988:Phosphodiesterase 4 Inhibitors; D010795:Phthalic Acids; D011799:Quinazolines; C583128:methyl 4-(((3-(6,7-dimethoxy-2-(methylamino)quinazolin-4-yl)phenyl)amino)carbonyl)benzoate; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4