The State of the Art in Selective PDE2A Inhibitor Design

Ende, Christopher W. am; Kormos, Bethany L.; Humphrey, John M.

doi:10.1002/9783527682348.ch06

Cited by 3 publications

(5 citation statements)

References 25 publications

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“…We then directed our attention to investigate the influence of ortho-fluorophenyl (phe-2) at the 1-position. In the case of BIT6 , having a 2-F-pyr-4 at the 8-position, a weakly lower potency towards PDE2A of 56% was observed, when compared to BIT1 , which is in accordance with the known positive PDE2A inhibitory effect of 2″-Cl in comparison to 2″-F [20,28]. A non-fluorinated pyridine (pyr-4 in BIT9 ) also maintained the inhibitory activity towards PDE2A of 80.5%, close to BIT1 (82.9%), however at the expense of increasing inhibition towards PDE10A and PDE4A (96.6% and 86.8% at a 1 μM inhibitor concentration) in contrast to BIT1 (32.4% and 58.6% at 1 μM).…”

Section: Resultssupporting

confidence: 69%

“…In this connection, another factor that contributes to the selectivity of BAY 60-7550 is a glutamine-switch mechanism [39], which is generally proposed for dual substrate-specific PDEs, such as PDE2A [1,39]. We assume that triazine N-5 in our scaffold might accept a hydrogen bond from Gln859 in a similar mode as described for the pyrazine portion in bioisosteric triazoloquinoxaline-based PDE2A inhibitors [16,20]. We further investigated the influence of different pyridinyl substituents at the 8-position on PDE2A inhibition while keeping the phe-1 fixed at the 1-position.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzo[e]imidazo[2,1-c][1,2,4]triazines as Phosphodiesterase 2A Inhibitors

et al. 2019

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Phosphodiesterase 2A (PDE2A) is highly expressed in distinct areas of the brain, which are known to be related to neuropsychiatric diseases. The development of suitable PDE2A tracers for Positron Emission Tomography (PET) would permit the in vivo imaging of the PDE2A and evaluation of disease-mediated alterations of its expression. A series of novel fluorinated PDE2A inhibitors on the basis of a Benzoimidazotriazine (BIT) scaffold was prepared leading to a prospective inhibitor for further development of a PDE2A PET imaging agent. BIT derivatives (BIT1–9) were obtained by a seven-step synthesis route, and their inhibitory potency towards PDE2A and selectivity over other PDEs were evaluated. BIT1 demonstrated much higher inhibition than other BIT derivatives (82.9% inhibition of PDE2A at 10 nM). BIT1 displayed an IC50 for PDE2A of 3.33 nM with 16-fold selectivity over PDE10A. This finding revealed that a derivative bearing both a 2-fluoro-pyridin-4-yl and 2-chloro-5-methoxy-phenyl unit at the 8- and 1-position, respectively, appeared to be the most potent inhibitor. In vitro studies of BIT1 using mouse liver microsomes (MLM) disclosed BIT1 as a suitable ligand for 18F-labeling. Nevertheless, future in vivo metabolism studies are required.

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Section: Resultssupporting

confidence: 69%

Section: Resultsmentioning

confidence: 99%

Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzo[e]imidazo[2,1-c][1,2,4]triazines as Phosphodiesterase 2A Inhibitors

et al. 2019

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“…Each PDE2A variant contains GAF-A and GAF-B domains in their respective N -terminus. Binding of the cGMP to GAF-B positively stimulates the hydrolysis of cAMP and reduces aldosterone secretion, which in turn allows PDE2A to orchestrate a “cross-talk” between cAMP and cGMP signaling cascades. , …”

Section: Dual-specific Pdesmentioning

confidence: 99%

“…As shown in Figure , various PDE2A inhibitors have been developed and evaluated in preclinical and clinical settings. , The very first known PDE2A selective inhibitor, adenine derivative EHNA (IC 50(PDE2A) = 800 nM), was not suitable for clinical development owing to its limited potency. A follow-up candidate, BAY-60–7550 (IC 50(PDE2A) = 4.7 ± 1 nM), enhanced long-term potentiation of synaptic transmission without altering basal synaptic transmission, and exhibited improved memory effects in rat studies.…”

Section: Dual-specific Pdesmentioning

confidence: 99%

“…Binding of the cGMP to GAF-B positively stimulates the hydrolysis of cAMP and reduces aldosterone secretion, which in turn allows PDE2A to orchestrate a "cross-talk" between cAMP and cGMP signaling cascades. 12,121 Drug Discovery. As shown in Figure 13, various PDE2A inhibitors have been developed and evaluated in preclinical and clinical settings.…”

Section: ■ Introductionmentioning

confidence: 99%

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Advances in Cyclic Nucleotide Phosphodiesterase-Targeted PET Imaging and Drug Discovery

et al. 2021

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Cyclic nucleotide phosphodiesterases (PDEs) control the intracellular concentrations of cAMP and cGMP in virtually all mammalian cells. Accordingly, the PDE family regulates a myriad of physiological functions, including cell proliferation, differentiation and apoptosis, gene expression, central nervous system function, and muscle contraction. Along this line, dysfunction of PDEs has been implicated in neurodegenerative disorders, coronary artery diseases, chronic obstructive pulmonary disease, and cancer development. To date, 11 PDE families have been identified; however, their distinct roles in the various pathologies are largely unexplored and subject to contemporary research efforts. Indeed, there is growing interest for the development of isoform-selective PDE inhibitors as potential therapeutic agents. Similarly, the evolving knowledge on the various PDE isoforms has channeled the identification of new PET probes, allowing isoform-selective imaging. This review highlights recent advances in PDE-targeted PET tracer development, thereby focusing on efforts to assess disease-related PDE pathophysiology and to support isoform-selective drug discovery.

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Design and Synthesis of Novel and Selective Phosphodiesterase 2 (PDE2a) Inhibitors for the Treatment of Memory Disorders

et al. 2017

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A series of potent and selective [1,2,4]triazolo[1,5-a]pyrimidine PDE2a inhibitors is reported. The design and improvement of the binding properties of this series was achieved using X-ray crystal structures in conjunction with careful analysis of electronic and structural requirements for the PDE2a enzyme. One of the lead compounds, compound 27 (DNS-8254), was identified as a potent and highly selective PDE2a enzyme inhibitor with favorable rat pharmacokinetic properties. Interestingly, the increased potency of compound 27 was facilitated by the formation of a halogen bond with the oxygen of Tyr827 present in the PDE2a active site. In vivo, compound 27 demonstrated significant memory enhancing effects in a rat model of novel object recognition. Taken together, these data suggest that compound 27 may be a useful tool to explore the pharmacology of selective PDE2a inhibition.

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The State of the Art in Selective PDE2A Inhibitor Design

Cited by 3 publications

References 25 publications

Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzo[e]imidazo[2,1-c][1,2,4]triazines as Phosphodiesterase 2A Inhibitors

Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzo[e]imidazo[2,1-c][1,2,4]triazines as Phosphodiesterase 2A Inhibitors

Advances in Cyclic Nucleotide Phosphodiesterase-Targeted PET Imaging and Drug Discovery

Design and Synthesis of Novel and Selective Phosphodiesterase 2 (PDE2a) Inhibitors for the Treatment of Memory Disorders

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