Memory-enhancing effects of GEBR-32a, a new PDE4D inhibitor holding promise for the treatment of Alzheimer’s disease

Abstract

Memory loss characterizes several neurodegenerative disorders, including Alzheimer’s disease (AD). Inhibition of type 4 phosphodiesterase (PDE4) and elevation of cyclic adenosine monophosphate (cAMP) has emerged as a promising therapeutic approach to treat cognitive deficits. However, PDE4 exists in several isoforms and pan inhibitors cannot be used in humans due to severe emesis. Here, we present GEBR-32a, a new PDE4D full inhibitor that has been characterized both in vitro and in vivo using biochemical, electrophysiological and behavioural analyses. GEBR-32a efficiently enhances cAMP in neuronal cultures and hippocampal slices. In vivo pharmacokinetic analysis shows that GEBR-32a is rapidly distributed within the central nervous system with a very favourable brain/blood ratio. Specific behavioural tests (object location and Y-maze continuous alternation tasks) demonstrate that this PDE4D inhibitor is able to enhance memory in AD transgenic mice and concomitantly rescues their hippocampal long-term potentiation deficit. Of great relevance, our preliminary toxicological analysis indicates that GEBR-32a is not cytotoxic and genotoxic, and does not seem to possess emetic-like side effects. In conclusion, GEBR-32a could represent a very promising cognitive-enhancing drug with a great potential for the treatment of Alzheimer’s disease.

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

“…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). …”

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

“…Another approach was to develop a full PDE4D inhibitor (Maastricht University/Columbia University/University of Genoa) with probably less affinity for the PDE4D isoforms involved in emesis [70]. This first compound Gebr-7b was effective in improving cognition in a mouse APP/PS1 model of AD, as was also found for the follow-up compound Gebr32a in Tg2576 mice [71]. Gebr-7b had no effect on hippocampal Aβ load [72].…”

New Hybrid Pyrazole and Imidazopyrazole Antinflammatory Agents Able to Reduce ROS Production in Different Biological Targets

“…The first series of PDE4Is synthesized by our research group showed a great anti- In the same years we developed a large library of phosphodiesterase type 4D inhibitors (PDE4DIs). Among them many compounds (particularly GEBR-54 [8] and GEBR-32a [9], Figure 2) showed interesting PDE4D3 selective inhibition, and in vitro and in vivo assays evidenced their great potential as memory and cognitive performance enhancers (particularly in AD) without causing side-effects, such as sedation or emesis, in comparison with other PDE4Is [8][9][10]. On the other hand, PDE4Is have been largely studied for their anti-inflammatory effects, particularly in autoimmune diseases such Molecules 2020, 25, 899 3 of 18 as psoriasis [11], asthma and chronic obstructive pulmonary disease (COPD) [12,13].…”

“…On the other hand, PDE4Is have been largely studied for their anti-inflammatory effects, particularly in autoimmune diseases such Molecules 2020, 25, 899 3 of 18 as psoriasis [11], asthma and chronic obstructive pulmonary disease (COPD) [12,13]. More recently, several evidences suggested PDE4Is also for neurodegenerative inflammatory diseases [9,14]. The first series of PDE4Is synthesized by our research group showed a great anti-inflammatory activity: in particular, compound GEBR-4a ( Figure 2) and some analogues were able to reduce the superoxide anion and to increase cAMP intracellular level in a dose dependent manner, activity strictly related to PDE4 inhibition [15].…”