Evaluation of the therapeutic index of a novel phosphodiesterase 4B - Selective inhibitor over phosphodiesterase 4D in mice

Phosphodiesterase 4 (pde4) inhibitors have been developed for the treatment of pulmonary inflammatory diseases,but their clinical use was dose-limited by mainly gastric adverse effects. recent studies suggested pde4b-selective inhibitors over pde4d are supposed to display a wider therapeutic index than subtype non-selective pde4 inhibitors such as roflumilast. compound a was identified as an orally active pde4b-selective inhibitor over pde4d both in humans (80-fold selective) and mice (29-fold selective). in this study,the therapeutic effects of compound a and roflumilast were evaluated on lipopolysaccaride (lps) injection-induced plasma tnf-α elevation and on lps inhalation-induced pulmonary neutrophilia in mice. the inhibitory effect on gastric emptying in mice was evaluated as a gastric adverse effect. the therapeutic index for tnf-α production (titnf= id50 in gastric emptying / id50 in lps injection-induced plasma tnf-α elevation) of compound a was larger than roflumilast (9.0 and 0.2,respectively),whereas the therapeutic index for pulmonary neutrophilia (ti neu= id50 in gastric emptying / id50 in lps inhalation-induced pulmonary neutrophilia) of compound a was comparable to roflumilast (1.0 and 0.5,respectively). in conclusion,the tineu of compound a was not superior compared to that of roflumilast in spite of its high selectivity for pde4b over pde4d in mice. © the japanese pharmacological society.