awd-12-281 and Inflammation

Chronic obstructive pulmonary disease (COPD) is a disease state characterized by airflow limitation that is usually progressive. In addition, an abnormal inflammatory response of the lungs to noxious particles or gases can be seen throughout the airways, parenchyma, and pulmonary vasculature. So far, anti-inflammatory medications (eg, inhaled corticosteroids) have failed to show a major effect on the decline of lung function in COPD patients. Novel anti-inflammatory therapies such as selective phosphodiesterase 4 (PDE4) inhibitors are in clinical development. Their potential role in the management of COPD is described in this review.. Some of the selective PDE4 inhibitors have demonstrated in vitro and in vivo anti-inflammatory activity on cells commonly linked to airway inflammation in COPD, such as neutrophils. While these agents seem to offer only a modest improvement in lung function compared with other bronchodilators, their anti-inflammatory effects appear to provide some substantial benefits in reducing exacerbations and improving health-related quality of life.. Based on the available data, the second generation of selective PDE4 inhibitors will likely provide additional therapeutic options for the management of COPD. These agents may become an important tool in the treatment of this disease, since they target three important components of COPD: airway obstruction, inflammation, and structural changes.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Amides; Aminopyridines; Benzamides; Carboxylic Acids; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclohexanecarboxylic Acids; Cyclopropanes; Humans; Indoles; Inflammation; Lung; Nitriles; Nucleotides, Cyclic; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Pulmonary Disease, Chronic Obstructive

elbion (formerly ASTA Medica) and GlaxoSmithKline are developing an inhaled formulation of AWD-12-281 for the potential treatment of chronic obstructive pulmonary disease (COPD). By May 2005, phase II trials of this 5-hydroxyindole PDE4 inhibitor for COPD were ongoing.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Administration, Inhalation; Administration, Topical; Amides; Aminopyridines; Animals; Benzamides; Clinical Trials as Topic; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclopropanes; Dermatitis, Atopic; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Indoles; Inflammation; Lipopolysaccharides; Ovalbumin; Phosphodiesterase Inhibitors; Psoriasis; Pulmonary Disease, Chronic Obstructive; Respiratory Tract Diseases; Structure-Activity Relationship

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.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Administration, Oral; Administration, Topical; Amides; Animals; Bronchodilator Agents; Carboxylic Acids; Cattle; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclohexanecarboxylic Acids; Cytokines; Dermatitis, Allergic Contact; Disease Models, Animal; Ear; Female; Indoles; Inflammation; Inflammation Mediators; Injections, Intraperitoneal; Mice; Mice, Inbred BALB C; Nitriles; Time Factors; Toluene