BAY-7081

Data supporting the use of BAY-7081 in biochemical settings are solid, it has demonstrated low nM potency, demonstrated selectivity and the details of the interactions with PDE8A known from co-crystal structures. Given the lack of cellular data it is difficult to evaluate its usefulness for cell experiments, i.e. while a 1 µM potency is claimed against overexpressed murine PDE9A in CHO cells these data are not available for evaluation. It would also be useful to understand the primary reason for a two orders of magnitude drop-off in potency between the biochemical and the cellular setting, especially in light of low plasma protein binding and the apparent lack of serum in the cited work that describes the cellular assay. There is convincing data on the in vitro pharmacokinetics and also demonstrated exposure with a short half-life in rat, however there is no data showing translation to in vivo effects - additional data is needed to understand whether this relates to the choice of disease model or from lack of exposure in the intended target tissue. It is recommended that such exposure is thoroughly established through additional PK studies before conducting any efficacy studies - making sure target coverage is ensured over a sufficient time period to achieve desired effects.