PT  - JOURNAL ARTICLE
AU  - H. Kuss
AU  - N. Hoefgen
AU  - S. Johanssen
AU  - T. Kronbach
AU  - C. Rundfeldt
TI  - In Vivo Efficacy in Airway Disease Models of <em>N-</em>(3,5-Dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic Acid Amide (AWD 12-281), a Selective Phosphodiesterase 4 Inhibitor for Inhaled Administration
AID  - 10.1124/jpet.103.053942
DP  - 2003 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 373--385
VI  - 307
IP  - 1
4099  - http://jpet.aspetjournals.org/content/307/1/373.short
4100  - http://jpet.aspetjournals.org/content/307/1/373.full
SO  - J Pharmacol Exp Ther2003 Oct 01; 307
AB  - N-(3,5-Dichloro-pyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic acid amide (AWD 12-281) is a highly potent and selective phosphodiesterase 4 (PDE4) inhibitor that was designed to have a metabolic profile that was optimized for topical administration. The aim of the current study was to explore the pharmacological profile of intratracheally administered AWD 12-281 in different models of asthma and chronic obstructive pulmonary disease (COPD) in comparison with steroids. To assess the anti-inflammatory potential of AWD 12-281, the antigen-induced cell infiltration in bronchoalveolar lavage fluid (BALF) of Brown Norway rats was determined. AWD 12-281 (ID50 of 7 μg/kg i.t.) as well as beclomethasone (0.1 μg/kg i.t.) suppresses late-phase eosinophilia when administered intrapulmonary. Furthermore, AWD 12-281 has also strong anti-inflammatory properties when tested in lipopolysaccharide-induced acute lung neutrophilia in Lewis rats (ID50 of 0.02 μg/kg i.t.), ferrets (ID50 of 10 μg/kg i.t.), and domestic pigs (2–4 mg/pig i.t. or 1 mg/kg i.v.). In pigs, AWD 12-281 was as effective as beclomethasone (0.4 mg/pig i.t.) and dexamethasone (0.28 mg/kg i.v.), although at 3 to 10 times the dosage. The bronchodilatory activity of AWD 12-281 was assessed in sensitized guinea pigs. AWD 12-281 (1.5 mg/kg i.t., 1-h pretreatment) inhibited allergen-induced bronchoconstriction by 68% (parameter airway resistance). In sensitized BP-2 mice AWD 12-281 abolished the allergen-induced bronchial hyperresponsiveness and eosinophilia in BALF, showing dose dependence. When given orally, i.v. or i.t., AWD 12-281 has a considerably lower emetic potential than cilomilast in ferrets and roflumilast in pigs. When given topically by inhalation, no emesis could be induced in dogs up to the highest feasible dose (15 mg/kg in 50% lactose blend). These results indicate that AWD 12-281 is a unique potential new drug for the topical treatment of asthma and COPD. The American Society for Pharmacology and Experimental Therapeutics