Abstract

We have investigated the bronchodilator and anti-inflammatory properties of roflumilast (3-cyclopropylmethoxy-4-difluoromethoxy-N-[3,5-dichloropyrid-4-yl]-benzamide), a novel, highly potent, and selective phosphodiesterase 4 (PDE4) inhibitor. Additionally, we compared the effects of roflumilast and itsN-oxide, the primary metabolite in vivo, with those of the PDE4 inhibitors piclamilast, rolipram, and cilomilast. Roflumilast inhibited the ovalbumin-evoked contractions of tracheal chains prepared from sensitized guinea pigs (EC₅₀ = 2 × 10⁻⁷ M) but showed no relaxant effect on tissues contracted spontaneously. In spasmogen-challenged rats and guinea pigs, intravenously administered roflumilast displayed bronchodilatory activity (ED₅₀ = 4.4 and 7.1 μmol/kg, respectively). Furthermore, roflumilast dose dependently attenuated allergen-induced bronchoconstriction in guinea pigs (ED₅₀ = 0.1 μmol/kg i.v.). Roflumilast given orally (ED₅₀ = 1.5 μmol/kg) showed equal potency to its N-oxide (ED₅₀ = 1.0 μmol/kg) but was superior to piclamilast (ED₅₀ = 8.3 μmol/kg), rolipram (ED₅₀ = 32.5 μmol/kg), and cilomilast (ED₅₀ = 52.2 μmol/kg) in suppressing allergen-induced early airway reactions. To assess the anti-inflammatory potential of orally administered roflumilast, antigen-induced cell infiltration, total protein, and TNFα concentration in bronchoalveolar lavage fluid of Brown Norway rats were determined. Roflumilast and its N-oxide equally inhibited eosinophilia (ED₅₀ = 2.7 and 2.5 μmol/kg, respectively), whereas the reference inhibitors displayed lower potency (ED₅₀ = 17–106 μmol/kg). Besides, orally administered roflumilast abrogated LPS-induced circulating TNFα in the rat (ED₅₀ = 0.3 μmol/kg), an effect shared by its N-oxide, with both molecules exhibiting 8-, 25-, and 310-fold superiority to piclamilast, rolipram, and cilomilast, respectively. These results, coupled with the in vitro effects of roflumilast on inflammatory cells, suggest that roflumilast represents a potential new drug for the treatment of asthma and chronic obstructive pulmonary disease.