Towards selective phosphodiesterase 2A (PDE2A) inhibitors: a patent review (2010 - present)

Abstract

Recent publications in the literature and in filed patent applications demonstrate the interest of pharmaceutical companies for PDE2A. This has increased the insights of its possible therapeutic role but the few clinical trials were terminated. Based on the ongoing interest in the field it is likely that new clinical trials can be expected and will unravel the therapeutic potential of PDE2A inhibition.

The neuroprotective and antidepressant‐like effects of Hcyb1, a novel selective PDE2 inhibitor

“…However, only cGMP level was significantly improved after Hcyb1 treatment for 10 minutes in the present study. A possible explanation is that PDE2 has slightly higher affinity for cGMP than cAMP in the hippocampus and exerts its action mainly via the control of intracellular second messengers, cGMP and, to a lesser extent, cAMP . Further study suggested that Hcyb1 increased both cAMP and cGMP levels after treatment for 24 hours, which was consistent with cell viability results.…”

“…Currently, mammalian PDEs comprise at least 11 gene families. Among them, PDE2 is a dual substrate enzyme which is highly expressed in various brain regions, including the cerebral cortex, hippocampus, amygdale, and striatum, implicating that PDE2 may play a critical role in emotion, perception, concentration, and cognition . Inhibition of PDE2 activity in the brain can lead to increased intracellular cAMP and cGMP and their downstream protein kinases, which activate transcription factors, ultimately regulate the expression of specific genes that are involved in the expression of depressive symptoms or symptom relief .…”

“…However, Bay 60‐7550 also potently inhibits PDE1 and has poor penetration into the brain, leading to the limit use of this drug simply in basic research, rather than clinical studies . During the last several years, many other potent PDE2A inhibitors with various degrees of selectivity have been developed as indicated by patent applications published from January 2010 to February 2016 . However, the early clinical trials of these PDE2 inhibitors were terminated, and the reasons were unclear .…”

Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets

“…It is also noteworthy that the present study identified genome-wide significant evidence implicating three phosphodiesterase genes: PDE1C , PDE2A , and PDE4D . In particular, there is growing interest in PDE2A inhibitors as potential agents for cognitive enhancement (Trabanco et al 2016), and evidence suggests that these agents may enhance synaptic plasticity via presynaptic modulation of cAMP hydrolysis (Fernández-Fernández et al 2015). PDE4D inhibition is also under investigatation as a potential therapy for neurodegenerative disease (Ricciarelli et al 2017).…”

PDE2A2 regulates mitochondria morphology and apoptotic cell death via local modulation of cAMP/PKA signalling

“…A phase I clinical trial examining a PDE2A inhibitor for the treatment of schizophrenia is currently ongoing (Takeda, 2015). Despite extensive evidence linking PDE2A to disease and the growing interest of pharmaceutical companies in PDE2A (Trabanco et al, 2016), a mechanistic understanding of the role of this enzyme in pathophysiology remains limited.…”