title: 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.affiliation: Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Buenteweg 17, D-30559 Hannover, Germany. wolfgang.baeumer@tiho-hannover.de
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bäumer
authors.forename: Gilbert
authors.initials: G
authors.lastname: Gorr
authors.forename: Joachim
authors.initials: J
authors.lastname: Hoppmann
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Ehinger
authors.forename: Chris
authors.initials: C
authors.lastname: Rundfeldt
authors.forename: Manfred
authors.initials: M
authors.lastname: Kietzmann
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000008:administration & dosage* / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000287:Administration, Topical; D000577:Amides / Q000627:therapeutic use*; D000818:Animals; D001993:Bronchodilator Agents / Q000008:administration & dosage; D002264:Carboxylic Acids; D002417:Cattle; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003509:Cyclohexanecarboxylic Acids; D016207:Cytokines / Q000737:chemistry; D017449:Dermatitis, Allergic Contact / Q000188:drug therapy* / Q000517:prevention & control*; D004195:Disease Models, Animal; D004423:Ear; D005260:Female; D007211:Indoles / Q000627:therapeutic use*; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control; D018836:Inflammation Mediators / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D009570:Nitriles; D013997:Time Factors; D014050:Toluene / Q000009:adverse effects
chemical_list: C470045:AWD 12-281; D000577:Amides; D001993:Bronchodilator Agents; D002264:Carboxylic Acids; D003509:Cyclohexanecarboxylic Acids; D016207:Cytokines; D007211:Indoles; D018836:Inflammation Mediators; D009570:Nitriles; D014050:Toluene; C433247:Cilomilast; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4