New insights into selective PDE4D inhibitors: 3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-dimethylmorpholino)-2-oxoethyl) oxime (GEBR-7b) structural development and promising activities to restore memory impairment

Brullo, Chiara; Ricciarelli, Roberta; Prickaerts, Jos; Arancio, Ottavio; Massa, Matteo; Rotolo, Chiara; Romussi, Alessia; Rebosio, Claudia; Marengo, Barbara; Pronzato, Maria Adelaide; Hagen, B.; Goethem, Nick P. van; D’Ursi, Pasqualina; Orro, Alessandro; Milanesi, Luciano; Guariento, Sara; Cichero, Elena; Fossa, Paola; Fedele, Ernesto; Bruno, Olga

doi:10.1016/j.ejmech.2016.08.018

Cited by 35 publications

(38 citation statements)

References 53 publications

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“…2). Of note, 100 μM GEBR-32a was able to cause a 12-fold increase of the forskolin-induced elevation of cAMP in cultured cells, while the same concentration of its parent compound 8a evoked only a 4-fold increase under the very same experimental conditions30, indicating a better cell membrane diffusion of the fluorinated derivative.…”

Section: Discussionmentioning

confidence: 88%

“…For example, GEBR-32a showed an IC 50 of 2.43 μM toward PDE4D3, whereas that of compound 8a was 7.60 μM30. Fluorine introduction had even more dramatic effects on BBB permeability, the brain/plasma ratio being extremely improved from 0.76 for compound 8a to 2.71 for GEBR-32a.…”

Section: Discussionmentioning

confidence: 98%

“…In this study, we present GEBR-32a, a novel PDE4D inhibitor deriving from the lead optimization process of compound 8a, which was recently synthesized and characterized in our laboratories30.…”

Section: Discussionmentioning

confidence: 99%

“…As inhibition of PDE4D activity has been consistently shown to ameliorate memory formation2628303839, GEBR-32a was trialled in two different behavioural tests, the object location task (OLT) and the Y-maze alternation task. To verify that fluorine introduction had not influenced the pro-cognitive properties of the parent compound 8a in normal adult mice30, we tested GEBR-32a under the same experimental conditions.…”

Section: Discussionmentioning

confidence: 99%

“…In this context, our group has recently synthesized and characterized several selective PDE4D full inhibitors, some of which showed cognitive-enhancing properties in rodents at doses that were devoid of emetic-like effects252627282930.…”

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confidence: 99%

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

Ricciarelli

Brullo

Prickaerts

et al. 2017

Sci Rep

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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.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Ricciarelli

Brullo

Prickaerts

et al. 2017

Sci Rep

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Design, synthesis, and pharmacological characterization of some 2‐substituted‐3‐phenyl‐quinazolin‐4(3H)‐one derivatives as phosphodiesterase inhibitors

Amin

Hegazy

George

et al. 2021

Archiv der Pharmazie

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Some 3‐phenyl‐quinazolin‐4(3H)‐one‐2‐thioethers (3a–e, 5a,b, 7a–e, 9a–d, 10a–d, and 12) along with 2‐aminoquinazoline derivatives 13a–c were prepared and screened for their in vitro phosphodiesterase (PDE) inhibitory activity. Some compounds such as 7d,e, 9a,b,d, 10a,d, and 13b exhibited promising activity as compared with the non‐selective PDE inhibitor IBMX. This inhibitory activity was validated by molecular docking in the active site of PDE7A and PDE4 to investigate their selectivity. Furthermore, the most active compound 10d (IC50 = 1.15 μM) was tested in vivo using behavioral tests. Compound 10d was able to pass the blood–brain barrier and improve scopolamine‐induced cognitive deficits. Therefore, this core can be considered as a promising scaffold for further optimization to obtain new compounds with better PDE7A selective inhibition.

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Scouting Different Phosphodiesterase 4 Inhibitor Chemotypes in Silico To Guide the Design of Anti‐inflammatory/Antioxidant Agents

et al. 2023

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During the last years, we developed a large library of new selective phosphodiesterase 4D inhibitors, maintaining the catechol portion of the well-known PDE4 inhibitor Rolipram, featuring different substitutions in place of the lactam group of this reference compound. Based on the X-ray analysis of PDE4 inhibitors (PDE4Is) previously synthesized by us and of naphthyridine-and naphthyridinone-containing derivatives exhibiting PDE4 inhibitory ability described in the literature, we designed and synthesized new compounds 1-3. All of them were screened in silico as putative PDE4Is, via molecular docking studies to exploit structural variation at the catechol group to gain further contacts especially with the flat aromatic residues (Phe506 and Phe538) of enzyme. Subsequent in silico prediction of ADMET properties and in vitro biological assays on platelets and endothelial cells are in good agreement with our previous data concerning the antioxidant/anti-inflammatory activity exhibited by our previous PDE4Is and similarly to other well-known PDE4Is.

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New insights into selective PDE4D inhibitors: 3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-dimethylmorpholino)-2-oxoethyl) oxime (GEBR-7b) structural development and promising activities to restore memory impairment

Cited by 35 publications

References 53 publications

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

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

Design, synthesis, and pharmacological characterization of some 2‐substituted‐3‐phenyl‐quinazolin‐4(3H)‐one derivatives as phosphodiesterase inhibitors

Scouting Different Phosphodiesterase 4 Inhibitor Chemotypes in Silico To Guide the Design of Anti‐inflammatory/Antioxidant Agents

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