In Vivo Efficacy in Airway Disease Models ofN-(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

Abstract

- [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 (ID 50 of 7 g/kg i.t.) as well as beclomethasone (0.1 g/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 (ID 50 of 0.02 g/kg i.t.), ferrets (ID 50 of 10 g/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 Pharmacology of Two Novel Long-Acting Phosphodiesterase 3/4 Inhibitors, RPL554 [9,10-Dimethoxy-2(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-Dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquinolin-4-one]

“…This extends previous work showing that the PDE4 inhibitors rolipram, roflumilast, cilomilast, and AWD 12-281 all attenuated allergeninduced pulmonary eosinophilia in the guinea pig (Banner et al, 1995;Underwood et al, 1998;Bundschuh et al, 2001;Kuss et al, 2003). In addition, we have demonstrated that RPL554 reduced the activation of eosinophils as assessed by the retention of EPO with eosinophils recovered in BAL.…”

“…A variety of selective PDE4 inhibitors, including AWD 12-281 (Kuss et al, 2003), cilomilast (Underwood et al, 1998), roflumilast (Bundschuh et al, 2001), and the mixed PDE3/4 inhibitor zardaverine (Underwood et al, 1994), have been reported to significantly attenuate acute bronchospasm induced by antigen in sensitized guinea pigs. Likewise, CDP840 , but not rolipram, attenuated allergen-induced bronchoconstriction in the rabbit.…”

“…Traditionally, systemic side effects of treatments for lung disease have been reduced by administering drugs by inhalation, and it would seem sensible to consider this approach also for the development of novel PDE inhibitors. Indeed, administration of the PDE3 inhibitor olprinone (Myou et al, 1999) or MKS492 (Bardin et al, 1998) in asthmatics provided significant bronchodilator activity without systemic side effects, and experimentally, delivery of PDE4 directly to the lung is not associated with gastrointestinal disturbances (Kuss et al, 2003). Furthermore, successful chemical strategies have been developed to improve the duration of action of short-acting drugs administered by inhalation, e.g., the modification of the short-acting ␤ 2 -adrenoceptor agonist salbutamol to give the longer acting salmeterol.…”

Bronchial hyperreactivity: pathogenesis and treatment options

“…Inhibition of PDE3 seems to be more accurate target, but inhibitors of PDE4 are used more frequently, as it is documented by the number of studies. Application of selective PDE4 inhibitors (rolipram, roflumilast, cilomilast, piclamilast) significantly reduced the count of immune cells, amount of subepithelial collagen and influenced the epithelial hyperplasia [52]. Rolipram, which belongs to the 1 st generation of PDE4 inhibitors, did not meet the criteria for safe drugs, because of serious side effects.…”

Phosphodiesterase 4 inhibition of 2-integrin adhesion caused by leukotriene B4 and TNF- in human neutrophils

“…Addition of salmeterol caused additive blockade of adhesion mediated by eotaxin, a G-protein-activating chemokine, in eosinophils [18]. Other investigations have demonstrated that inhibition of PDE4 attenuates airway hyperresponsiveness and airway inflammation in sensitised mice [19,20]. Several studies have demonstrated attenuation of airway inflammation and airway reactivity by interaction of salmeterol with corticosteroids and steroid-sparing effects of theophylline [21,22]; however, little is known about the mechanism of action of PDE4 in b 2 -integrin-mediated adhesion in human PMNs.…”