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: Naoto Ishii, Manabu Shirato, Hisashi Wakita, Kazuki Miyazaki, Yasutaka Takase, Osamu Asano, Kazutomi Kusano, Eiichi Yamamoto, Chiharu Inoue, Ieharu Hishinuma
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 346 Issue 1 Pg. 105-12 (Jul 2013) ISSN: 1521-0103 [Electronic] United States
• PMID: 23674603 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antipruritics
• Cell Adhesion Molecules
• Cytokines
• Phosphodiesterase 4 Inhibitors
• Phthalic Acids
• Quinazolines
• methyl 4-(((3-(6,7-dimethoxy-2-(methylamino)quinazolin-4-yl)phenyl)amino)carbonyl)benzoate
• Cyclic Nucleotide Phosphodiesterases, Type 4

Topics

• Administration, Topical
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Antipruritics (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Cell Adhesion Molecules (antagonists & inhibitors, metabolism)
• Cyclic Nucleotide Phosphodiesterases, Type 4 (chemistry, metabolism)
• Cytokines (antagonists & inhibitors, metabolism)
• Dermatitis, Atopic (blood, drug therapy, immunology, metabolism)
• Disease Models, Animal
• Female
• Humans
• Lymphocytes (drug effects, immunology, metabolism)
• Male
• Metabolic Clearance Rate
• Mice
• Mice, Inbred Strains
• Monocytes (drug effects, immunology, metabolism)
• Phosphodiesterase 4 Inhibitors (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Phthalic Acids (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Quinazolines (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Skin (drug effects, immunology, metabolism)
• Tissue Distribution