In vivo efficacy in airway disease models of roflumilast, a novel orally active PDE4 inhibitor

We have investigated the bronchodilator and anti-inflammatory properties of roflumilast (3-cycloproplymethoxy-4-difluorome-thoxy-N-[3,5-dichloropyrid- 4-yl]-benzamide), a novel, highly potent, and selective phosphosdiesterase 4 (PDE4) inhibitor. Additionally, we compared the effects of roflumilast an d its N-oxide, the primary metabolite in vivo, with those of the PDE4 inhib itors piclamilast, rolipram, and cilomilast. Roflumilast inhibited from sen sitized guinea pigs (EC50 = 2 x 10(-7) M) but showed no relaxant effect on tissues contracted spontaneously. In spasmogen-challenged rats and guinea p igs, intravenously administered roflumilast displayed bronchodilatory activ ity (ED50 = 4.4 and 7.1 mu mol/kg, respectively). Furthermore, roflumilast dose dependently attenuated allergen-induced bronchoconstriction in guinea pigs (ED50 = 0.1 mu mol/kg i.v.). Roflumilast given orally (ED50 = 1.5 mu m ol/kg) showed equal potency to its N-oxide (ED50 = 1.0 mu mol/kg) but was s uperior to piclamilast (ED50 = 8.3 mu mol/kg), rolipram (ED50 = 32.5 mu mol /kg), and cilomilast (ED50 = 52.2 mu mol/kg) in suppressing allergen-induce d early airway reactions. To assess the anti-inflammatory potential of oral ly administered roflumilast, antigen-induced cell infiltration, total prote in, and TNF alpha concentration in bronchoalveolar lavage fluid of Brown No rway rats were determined. Roflumilast and its N-oxide equally inhibited eo sinophilia (ED50 = 2.7 and 2.5 mu mol/kg, respectively), whereas the refere nce inhibitors displayed lower potency (ED50 = 17-106 mu mol/kg). Besides, orally administered roflumilast abrogated LPS-induced circulating TNF alpha in the rat (ED50 = 0.3 mu mol/kg), an effect shared by its N-oxide, with b oth 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 roflumilas t represents a potential new drug for the treatment of asthma and chronic o bstructive pulmonary disease.