Evaluation of the Therapeutic Index of a Novel Phosphodiesterase 4B–Selective Inhibitor Over Phosphodiesterase 4D in Mice

Abstract 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 (TI TNF = ID 50 in gastric emptying / ID 50 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 = ID 50 in gastric emptying / ID 50 in LPS inhalation–induced pulmonary neutrophilia) of compound A was comparable to roflumilast (1.0 and 0.5, respectively). In conclusion, the TI Neu of compound A was not superior compared to that of roflumilast in spite of its high selectivity for PDE4B over PDE4D in mice.