AWD 12-281, a highly selective phosphodiesterase 4 inhibitor, is effective in the prevention and treatment of inflammatory reactions in a model of allergic dermatitis.

Abstract

AWD 12-281 (N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide), a phosphodiesterase 4 inhibitor, which is optimized for topical administration, was tested in a model of allergic dermatitis in mice. To obtain an allergic dermatitis, BALB/c mice were sensitized to toluene-2,4-diisocyanate (TDI). The allergic reaction was challenged by topical administration of TDI onto the mice ears. AWD 12-281 was tested for its anti-inflammatory potential by oral, intraperitoneal and topical administration. The phosphodiesterase 4 inhibitor, cilomilast (SB 207499), and/or the corticosteroid, diflorasone diacetate, were used as reference compounds. Given orally and intraperitoneally 2 h before as well as 5 and 24 h after TDI challenge, AWD 12-281 showed no, or only a transient inhibition of the allergen-induced ear swelling, whereas cilomilast significantly inhibited this ear swelling. Applied topically onto the ears before TDI challenge, AWD 12-281, cilomilast and diflorasone diacetate caused total inhibition of ear swelling 24 h after challenge, confirmed by a decrease of the pro-inflammatory cytokines interleukin-4, interleukin-6 and macrophage inhibitory protein-2. Administered topically after TDI challenge as therapeutic intervention, AWD 12-281 and diflorasone diacetate caused significant inhibition of ear swelling; cilomilast failed to do so. These results indicate that topically administered AWD 12-281 may be potent in the prevention and treatment of allergic/inflammatory skin diseases.

• Authors: Wolfgang Bäumer, Gilbert Gorr, Joachim Hoppmann, Andreas M Ehinger, Chris Rundfeldt, Manfred Kietzmann
• Journal: The Journal of pharmacy and pharmacology (J Pharm Pharmacol) Vol. 55 Issue 8 Pg. 1107-14 (Aug 2003) ISSN: 0022-3573 [Print] England
• PMID: 12956900 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AWD 12-281
• Amides
• Bronchodilator Agents
• Carboxylic Acids
• Cyclohexanecarboxylic Acids
• Cytokines
• Indoles
• Inflammation Mediators
• Nitriles
• Toluene
• Cilomilast
• 3',5'-Cyclic-AMP Phosphodiesterases
• Cyclic Nucleotide Phosphodiesterases, Type 4

Topics

• 3',5'-Cyclic-AMP Phosphodiesterases (administration & dosage, antagonists & inhibitors)
• Administration, Oral
• Administration, Topical
• Amides (therapeutic use)
• Animals
• Bronchodilator Agents (administration & dosage)
• Carboxylic Acids
• Cattle
• Cyclic Nucleotide Phosphodiesterases, Type 4
• Cyclohexanecarboxylic Acids
• Cytokines (chemistry)
• Dermatitis, Allergic Contact (drug therapy, prevention & control)
• Disease Models, Animal
• Ear
• Female
• Indoles (therapeutic use)
• Inflammation (chemically induced, prevention & control)
• Inflammation Mediators (therapeutic use)
• Injections, Intraperitoneal
• Mice
• Mice, Inbred BALB C
• Nitriles
• Time Factors
• Toluene (adverse effects)