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

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 24h 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.