In vivo efficacy in airway disease models of N-(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.
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 microg/kg i.t.) as well as beclomethasone (0.1microg/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 microg/kg i.t.), ferrets (ID50 of 10 microg/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.
Kuss
H
H
Department of Pharmacology, elbion AG, Radebeul, Germany. hildegard.kuss@elbion.de
Hoefgen
N
N
Johanssen
S
S
Kronbach
T
T
Rundfeldt
C
C
D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000280:Administration, Inhalation; D000485:Allergens; D000577:Amides / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D016084:Bronchoconstriction; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004285:Dogs; D004802:Eosinophilia / Q000139:chemically induced / Q000517:prevention & control; D005289:Ferrets; D006168:Guinea Pigs; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D008070:Lipopolysaccharides; D008171:Lung Diseases / Q000150:complications / Q000188:drug therapy*; D051379:Mice; D009504:Neutrophils / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D013552:Swine; D013997:Time Factors; D016896:Treatment Outcome; D014839:Vomiting / Q000209:etiology
C470045:AWD 12-281; D000485:Allergens; D000577:Amides; D007211:Indoles; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4