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

• Published in: Journal of pharmacy and pharmacology 2003-08, Vol.55 (8), p.1107-1114
• Main Authors: Bäumer, Wolfgang, Gorr, Gilbert, Hoppmann, Joachim, Ehinger, Andreas M., Rundfeldt, Chris, Kietzmann, Manfred
• Format: Article
• Language: English
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - administration & dosage; 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; Administration, Oral; Administration, Topical; Amides - therapeutic use; Animals; Biological and medical sciences; Bronchodilator Agents - administration & dosage; Carboxylic Acids; Cattle; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclohexanecarboxylic Acids; Cytokines - chemistry; Dermatitis, Allergic Contact - drug therapy; Dermatitis, Allergic Contact - prevention & control; Disease Models, Animal; Ear; Female; Histamine and antagonists. Allergy; Indoles - therapeutic use; Inflammation - chemically induced; Inflammation - prevention & control; Inflammation Mediators - therapeutic use; Injections, Intraperitoneal; Medical sciences; Mice; Mice, Inbred BALB C; Nitriles; Pharmacology. Drug treatments; Time Factors; Toluene - adverse effects
• ISSN: 0022-3573; 2042-7158
• DOI: 10.1211/0022357021585

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 inflammatory 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.