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.