Pyrido[4,3-<i>e</i>][1,2,4]triazolo[4,3-<i>a</i>]pyrazines as Selective, Brain Penetrant Phosphodiesterase 2 (PDE2) Inhibitors

Rombouts, Frederik; Tresadern, Gary; Buijnsters, Peter; Langlois, Xavier; Tovar, Fulgencio; Steinbrecher, Thomas; Vanhoof, Greet; Somers, Marijke; Andrés, José-Ignacio; Trabanco, Andrés A.

doi:10.1021/ml500463t

Cited by 53 publications

(49 citation statements)

References 15 publications

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“…Therefore, to have confidence that our docking poses were realistic, we applied free energy perturbation (FEP) methodology to predict the difference in binding energy between the two compounds and compared the result to the experimental value. This approach is particularly well suited given the small structural change between (2 S ,3 R )‐ 11 and ( S )‐ 26 30…”

Section: Resultsmentioning

confidence: 99%

Structural Biology of Cisplatin Complexes with Cellular Targets: The Adduct with Human Copper Chaperone Atox1 in Aqueous Solution

Calandrini

Nguyen

Arnesano

et al. 2014

Chemistry A European J

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Cisplatin is one of the most used anticancer drugs. Its cellular influx and delivery to target DNA may involve the copper chaperone Atox1 protein. Although the mode of binding is established by NMR spectroscopy measurements in solution-the Pt atom binds to Cys12 and Cys15 while retaining the two ammine groups-the structural determinants of the adduct are not known. Here a structural model by hybrid Car-Parrinello density functional theory-based QM/MM simulations is provided. The platinated site minimally modifies the fold of the protein. The calculated NMR and CD spectral properties are fully consistent with the experimental data. Our in silico/in vitro approach provides, together with previous studies, an unprecedented view into the structural biology of cisplatin-protein adducts.

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Section: Resultsmentioning

confidence: 99%

Structural Biology of Cisplatin Complexes with Cellular Targets: The Adduct with Human Copper Chaperone Atox1 in Aqueous Solution

Calandrini

Nguyen

Arnesano

et al. 2014

Chemistry A European J

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“…In addition, differences in PDE2A enzyme levels in patients versus healthy controls can be established (18). A PET PDE2A ligand might also be useful for assessment of agents that increase cGMP levels, such as a PDE10 inhibitor, which raised cGMP, activating PDE2A through the GAF domain (19). Thus, a PDE2A PET ligand may be useful to identify signaling interactions between pathways that alter cGMP and cAMP.…”

Section: Discussionmentioning

confidence: 99%

First-in-Human Assessment of the Novel PDE2A PET Radiotracer ¹⁸F-PF-05270430

et al. 2016

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This was a first-in-human study of the novel phosphodiesterase-2A (PDE2A) PET ligand 18 F-PF-05270430. The primary goals were to determine the appropriate tracer kinetic model to quantify brain uptake and to examine the within-subject test-retest variability. Methods: In advance of human studies, radiation dosimetry was determined in nonhuman primates. Six healthy male subjects participated in a testretest protocol with dynamic scans and metabolite-corrected input functions. Nine brain regions of interest were studied, including the striatum, white matter, neocortical regions, and cerebellum. Multiple modeling methods were applied to calculate volume of distribution (V T ) and binding potentials relative to the nondisplaceable tracer in tissue (BP ND ), concentration of tracer in plasma (BP P ), and free tracer in tissue (BP F ). The cerebellum was selected as a reference region to calculate binding potentials. Results: The dosimetry study provided an effective dose of less than 0.30 mSv/MBq, with the gallbladder as the critical organ; the human target dose was 185 MBq. There were no adverse events or clinically detectable pharmacologic effects reported. Tracer uptake was highest in the striatum, followed by neocortical regions and white matter, and lowest in the cerebellum. Regional time-activity curves were well fit by multilinear analysis-1, and a 70-min scan duration was sufficient to quantify V T and the binding potentials. BP ND , with mean values ranging from 0.3 to 0.8, showed the best intrasubject and intersubject variability and reliability. Testretest variability in the whole brain (excluding the cerebellum) of V T , BP ND , and BP P were 8%, 16%, and 17%, respectively. Conclusion: 18 F-PF-05270430 shows promise as a PDE2A PET ligand, albeit with low binding potential values.

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“…This led work to focus on the optimization of pharmacokinetic properties of PDE2 inhibitors. Zhang et al tried to discover selective potent PDE2A inhibitors with improved pharmacokinetic properties [60][61][62][63][64][65][66][67]. In their study, they described the identiication of novel PDE2A inhibitors by structure-based virtual screening.…”

Section: Pde2 Inhibitorsmentioning

confidence: 99%

Computational Approaches in the Development of Phosphodiesterase Inhibitors

Gaurav¹,

Xing²,

Al-Nema³

2017

Quantitative Structure-Activity Relationship

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Computational drug design tools have become indispensable in the quest for new drugs. There is hardly any drug discovery program where computational methods are not employed, be it structure-based or ligand-based methods. Numerous drug targets have been explored for discovery of new drugs using computational methods. In recent times, discovery of newer and selective phosphodiesterase as medications for inlammatory disorders, CNS disorders, and many other diseases has been the focus of many research groups worldwide. Most of these groups have employed computational methods of drug design and discovery at diferent stages of their research. This chapter reviews the reported application of computational methods used in the discovery and development of phosphodiesterase inhibitors.

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Pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines as Selective, Brain Penetrant Phosphodiesterase 2 (PDE2) Inhibitors

Cited by 53 publications

References 15 publications

Structural Biology of Cisplatin Complexes with Cellular Targets: The Adduct with Human Copper Chaperone Atox1 in Aqueous Solution

Structural Biology of Cisplatin Complexes with Cellular Targets: The Adduct with Human Copper Chaperone Atox1 in Aqueous Solution

First-in-Human Assessment of the Novel PDE2A PET Radiotracer ¹⁸F-PF-05270430

Computational Approaches in the Development of Phosphodiesterase Inhibitors

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Pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines as Selective, Brain Penetrant Phosphodiesterase 2 (PDE2) Inhibitors

Cited by 53 publications

References 15 publications

Structural Biology of Cisplatin Complexes with Cellular Targets: The Adduct with Human Copper Chaperone Atox1 in Aqueous Solution

Structural Biology of Cisplatin Complexes with Cellular Targets: The Adduct with Human Copper Chaperone Atox1 in Aqueous Solution

First-in-Human Assessment of the Novel PDE2A PET Radiotracer 18F-PF-05270430

Computational Approaches in the Development of Phosphodiesterase Inhibitors

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Product

Resources

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First-in-Human Assessment of the Novel PDE2A PET Radiotracer ¹⁸F-PF-05270430