Selective inhibitors of phosphodiesterases: therapeutic promise for neurodegenerative disorders

Umar, Tarana; Hoda, Nasimul

doi:10.1039/c5md00419e

Cited by 15 publications

(15 citation statements)

References 143 publications

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“…This specific distribution indicates a role of PDE2A in the modulation of complex neuronal processes, such as learning, concentration, memory, emotion, depression, anxiety, and CNS related disorder [10,13,14]. The pharmacological inhibition of PDE2A has been evaluated in preclinical studies, thus suggesting PDE2A inhibitors as a potential treatment for neurodegenerative diseases, such as Alzheimer’s disease, schizophrenia, and dementia [15,16]. PDE2A inhibition has the potential to prolong the duration of cAMP- and cGMP-dependent signaling pathways, eventually improving neural plasticity and memory function [3,13,17].…”

Section: Introductionmentioning

confidence: 99%

Radiosynthesis and Biological Investigation of a Novel Fluorine-18 Labeled Benzoimidazotriazine-Based Radioligand for the Imaging of Phosphodiesterase 2A with Positron Emission Tomography

et al. 2019

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A specific radioligand for the imaging of cyclic nucleotide phosphodiesterase 2A (PDE2A) via positron emission tomography (PET) would be helpful for research on the physiology and disease-related changes in the expression of this enzyme in the brain. In this report, the radiosynthesis of a novel PDE2A radioligand and the subsequent biological evaluation were described. Our prospective compound 1-(2-chloro-5-methoxy phenyl)-8-(2-fluoropyridin-4-yl)-3- methylbenzo[e]imidazo[5,1-c][1,2,4]triazine, benzoimidazotriazine (BIT1) (IC50 PDE2A = 3.33 nM; 16-fold selectivity over PDE10A) was fluorine-18 labeled via aromatic nucleophilic substitution of the corresponding nitro precursor using the K[18F]F-K2.2.2-carbonate complex system. The new radioligand [18F]BIT1 was obtained with a high radiochemical yield (54 ± 2%, n = 3), a high radiochemical purity (≥99%), and high molar activities (155–175 GBq/μmol, n = 3). In vitro autoradiography on pig brain cryosections exhibited a heterogeneous spatial distribution of [18F]BIT1 corresponding to the known pattern of expression of PDE2A. The investigation of in vivo metabolism of [18F]BIT1 in a mouse revealed sufficient metabolic stability. PET studies in mouse exhibited a moderate brain uptake of [18F]BIT1 with a maximum standardized uptake value of ~0.7 at 5 min p.i. However, in vivo blocking studies revealed a non-target specific binding of [18F]BIT1. Therefore, further structural modifications are needed to improve target selectivity.

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Section: Introductionmentioning

confidence: 99%

Radiosynthesis and Biological Investigation of a Novel Fluorine-18 Labeled Benzoimidazotriazine-Based Radioligand for the Imaging of Phosphodiesterase 2A with Positron Emission Tomography

et al. 2019

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“…In Alzheimer's disease (AD), these targets represent an alternative to classical amyloid candidate targets. Among the 11 different phosphodiesterase isoenzymes, inhibition of PDE5 (cGMP-specific) by FDA approved drugs for treating erectile dysfunction like sildenafil (1), vardenafil (2), and tadalafil (3) has been shown to restore cognitive function or/and enhance synaptic plasticity. 7−9 The underlying mechanism is the activation of gene transcription triggered by protein kinase A (PKA)dependent phosphorylation of cAMP/cGMP response element-binding (CREB), which is the main modulator for longterm memory (LTM) formation.…”

Section: ■ Introductionmentioning

confidence: 99%

Impact of Scaffold Exploration on Novel Dual-Acting Histone Deacetylases and Phosphodiesterase 5 Inhibitors for the Treatment of Alzheimer’s Disease

Sánchez‐Arias¹,

Rabal²,

Cuadrado‐Tejedor

et al. 2016

ACS Chem. Neurosci.

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A novel systems therapeutics approach, involving simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylase (HDAC), has been validated as a potentially novel therapeutic strategy for the treatment of Alzheimer's disease (AD). First-in-class dual inhibitors bearing a sildenafil core have been very recently reported, and the lead molecule 7 has proven this strategy in AD animal models. Because scaffolds may play a critical role in primary activities and ADME-Tox profiling as well as on intellectual property, we have explored alternative scaffolds (vardenafil- and tadalafil-based cores) and evaluated their impact on critical parameters such as primary activities, permeability, toxicity, and in vivo (pharmacokinetics and functional response in hippocampus) to identify a potential alternative lead molecule bearing a different chemotype for in vivo testing.

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“…Moreover, decreased levels of cGMP in the cerebrospinal fluid of patients with AD were observed which are assumed to be associated with the cognitive decline and amyloid pathology [ 14 ]. Given the lack of effective treatments for AD, PDE5 inhibitors as have been proposed as potential alternative cognitive enhancers [ 13 , 15 ]. The effectiveness of repeated PDE5 inhibitor treatment has been shown in several mouse models of AD and physiological aging [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Development of a New Radiofluorinated Quinoline Analog for PET Imaging of Phosphodiesterase 5 (PDE5) in Brain

et al. 2016

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Phosphodiesterases (PDEs) are enzymes that play a major role in cell signalling by hydrolysing the secondary messengers cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP) throughout the body and brain. Altered cyclic nucleotide-mediated signalling has been associated with a wide array of disorders, including neurodegenerative disorders. Recently, PDE5 has been shown to be involved in neurodegenerative disorders such as Alzheimer’s disease, but its precise role has not been elucidated yet. To visualize and quantify the expression of this enzyme in brain, we developed a radiotracer for specific PET imaging of PDE5. A quinoline-based lead compound has been structurally modified resulting in the fluoroethoxymethyl derivative ICF24027 with high inhibitory activity towards PDE5 (IC50 = 1.86 nM). Radiolabelling with fluorine-18 was performed by a one-step nucleophilic substitution reaction using a tosylate precursor (RCY(EOB) = 12.9% ± 1.8%; RCP > 99%; SA(EOS) = 70–126 GBq/μmol). In vitro autoradiographic studies of [18F]ICF24027 on different mouse tissue as well as on porcine brain slices demonstrated a moderate specific binding to PDE5. In vivo studies in mice revealed that [18F]ICF24027 was metabolized under formation of brain penetrable radiometabolites making the radiotracer unsuitable for PET imaging of PDE5 in brain.

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Selective inhibitors of phosphodiesterases: therapeutic promise for neurodegenerative disorders

Abstract: PDE inhibitors: significant contributors to the treatment of neurodegenerative diseases.

Cited by 15 publications

References 143 publications

Radiosynthesis and Biological Investigation of a Novel Fluorine-18 Labeled Benzoimidazotriazine-Based Radioligand for the Imaging of Phosphodiesterase 2A with Positron Emission Tomography

Radiosynthesis and Biological Investigation of a Novel Fluorine-18 Labeled Benzoimidazotriazine-Based Radioligand for the Imaging of Phosphodiesterase 2A with Positron Emission Tomography

Impact of Scaffold Exploration on Novel Dual-Acting Histone Deacetylases and Phosphodiesterase 5 Inhibitors for the Treatment of Alzheimer’s Disease

Development of a New Radiofluorinated Quinoline Analog for PET Imaging of Phosphodiesterase 5 (PDE5) in Brain

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