BAY 73-6691 is the first potent inhibitor developed against phosphodiesterase 9 (PDE9). PDE9, a novel family of PDEs, has high selectivity and binding affinity for cGMP (Km = 0.07-0.17 μM). Furthermore, cGMP levels in the brain play an important role in learning and memory, thus the localization of PDE9 in the brain makes it a suitable target to study these processes.
The recent generation of a PDE9 reporter cell line, whereby intracellular levels of cGMP can be observed by aequorin luminescence, enabled characterization of this inhibitor. The inhibitory activity of BAY 73-6691 is selective for human and murine PDE9 in vitro
(IC50 values 55 nM and 100 nM respectively).
BAY 73-6691 has been studied as a potential treatment for Alzheimer’s disease. Since oxidative stress is frequently related to the development of Alzheimer’s disease, the antioxidant properties of BAY 73-6691 was investigated in vitro
and in vivo
. The deposition of amyloid β-protein (Aβ) in neuritic plaques is a characteristic feature of Alzheimer’s disease. Treatment with BAY 73-6691 in Aβ-stimulated resulted in human neuroblastoma cells and mice improved cell viability and reduced levels of malondialdehyde (an indicator of oxidative stress severity) and thus demonstrated its neuroprotective and antioxidant effects. Furthermore, BAY 73-6691 protected mice from Aβ-mediated negative effects on spatial memory and hippocampal neurons.
A suggested mode of action to explain the protective effects of BAY 73-6691 from oxidative stress is its inhibitory action on cGMP degradation. The subsequent increase in cGMP-mediated nitric oxide (NO)-dependent signaling results in reduced free superoxide radicals that otherwise form toxic reactive species. Furthermore, this theory is supported by the finding that treatment with BAY 73-6691 led to raised levels of NO synthesis.