Phosphodiesterase 10A inhibitors: a 2009 – 2012 patent update

Kehler, Jan

doi:10.1517/13543776.2012.739157

Cited by 35 publications

(18 citation statements)

References 29 publications

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“…A proof of concept study by Pfizer in which MP-10 (PF-2545920) was evaluated for its antipsychotic efficacy resulted in negative results. 49 On the basis of the findings in the present study, it is unlikely that altered PDE10A levels in the patients due to prior exposure to antipsychotics undelie the negative result. However, we also have no knowledge on the baseline PDE10A expression levels in patients diagnosed with schizophrenia.…”

Section: Discussionmentioning

confidence: 51%

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Effect of chronic antipsychotic treatment on striatal phosphodiesterase 10A levels: a [11C]MP-10 PET rodent imaging study with ex vivo confirmation

et al. 2014

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A number of phosphodiesterase 10A (PDE10) inhibitors are about to undergo clinical evaluation for their efficacy in treating schizophrenia. As phosphodiesterases are in the same signalling pathway as dopamine D2 receptors, it is possible that prior antipsychotic treatment could influence these enzyme systems in patients. Chronic, in contrast to acute, antipsychotic treatment has been reported to increase brain PDE10A levels in rodents. The aim of this study was to confirm these findings in a manner that can be translated to human imaging studies to understand its consequences. Positron emission tomography (PET) scanning was used to evaluate PDE10A enzyme availability, after chronic haloperidol administration, using a specific PDE10A ligand ([11C]MP-10). The binding of [11C]MP-10 in the striatum and the cerebellum was measured in rodents and a simplified reference tissue model (SRTM) with cerebellum as the reference region was used to determine the binding potential (BPND). In rats treated chronically with haloperidol (2 mg kg−1 per day), there was no significant difference in PDE10A levels compared with the vehicle-treated group (BPND±s.d.: 3.57±0.64 versus 2.86±0.71). Following PET scans, ex vivo analysis of striatal brain tissue for PDE10A mRNA (Pde10a) and PDE10A enzyme activity showed no significant difference. Similarly, the PDE10A protein content determined by western blot analysis was similar between the two groups, contrary to an earlier finding. The results of the study indicate that prior exposure to antipsychotic medication in rodents does not alter PDE10A levels.

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Section: Discussionmentioning

confidence: 51%

“…The result of this study will help guide clinical trials not only for schizophrenia therapeutics but also for other neuropsychiatric disorders, especially Huntington's disease, where concomitant antipsychotic use is prevalent. 49 …”

Section: Discussionmentioning

confidence: 99%

Effect of chronic antipsychotic treatment on striatal phosphodiesterase 10A levels: a [11C]MP-10 PET rodent imaging study with ex vivo confirmation

et al. 2014

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“…PDE10A is highly expressed in MSNs of the mammalian striatum (Soderling and Beavo, 2000, Seeger et al, 2003, Xie et al, 2006, and regulates the output function of both the direct and indirect pathways (Siuciak et al, 2006). Dysfunction of the corticostriatal circuit has been implicated in various central nervous system (CNS) disorders including schizophrenia; thus, pharmacological inhibition of PDE10A and the resulting activation of the corticostriatal circuit could be a promising therapeutic approach for these disorders (Kehler andNielsen, 2011, Kehler, 2013).…”

Section: Introductionmentioning

confidence: 99%

TAK-063, a phosphodiesterase 10A inhibitor, modulates neuronal activity in various brain regions in phMRI and EEG studies with and without ketamine challenge

et al. 2016

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TAK-063 is a selective phosphodiesterase 10A (PDE10A) inhibitor that produces potent antipsychotic-like and pro-cognitive effects at 0.3mg/kg (26% PDE10A occupancy in rats) or higher in rodents through the balanced activation of the direct and indirect pathways of striatal medium spiny neurons (MSNs). In this study, we evaluated the specific binding of TAK-063 using in vitro autoradiography (ARG) and the modulation of brain activity using pharmacological magnetic resonance imaging (phMRI) and electroencephalography (EEG). [H]TAK-063 significantly accumulated in the caudate-putamen (CPu), ventral pallidum (VP), substantia nigra (SN), hippocampus (Hipp), and amygdala (Amy), but not in the frontal cortex (Fcx), brainstem (Bs), or cerebellum (Cb) in an ARG study using rat brain sections. [H]TAK-063 accumulation in the CPu was more than eighteen-fold higher than that in the Hipp and Amy. TAK-063 at 0.3mg/kg increased the blood oxygenation level-dependent (BOLD) signal in the striatum and Amy, and decreased it in the Fcx in a phMRI study with anesthetized rats. TAK-063 at 0.3mg/kg significantly reduced the ketamine-induced increase in EEG gamma power both in awake and anesthetized rats. TAK-063 at 0.2mg/kg (35% PDE10A occupancy in monkeys) also reduced the ketamine-induced increase in EEG gamma power in awake monkeys. In line with the EEG data, TAK-063 at 0.3mg/kg reversed the ketamine-induced BOLD signal changes in the cortex, Bs, and Cb in a phMRI study with anesthetized rats. These data suggest that TAK-063 at about 30% PDE10A occupancy modulates activities of multiple brain regions through activation of neuronal circuits in rats and monkeys.

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“…Although the history of PDE10A is now more than 13 years old, it is relatively recent in terms of psychotropic development targets. Several pharmaceutical companies have developed clinical programs that attempt to validate the therapeutic potential of PDE10A inhibitors [17] the majority of firms focused on the treatment of schizophrenia in light of the observed preclinical results [18]. Indeed, these animal findings suggest that PDE10A inhibitors may have antipsychotic, procognitive and positive effects in negative symptoms.…”

Section: Inhibitors Of Phosphodiesterase 10amentioning

confidence: 99%

The Contribution of Aluminium to Alzheimer�s disease: A Neuropathological Investigation of Renal Dialysis Cases

Hall¹,

Patro²,

Morris³

2018

J Neurosci Neurosurg

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The development of psychotropic has slowed over the last two decades for essentially economic reasons; the drug industry has invested more in the field of oncology and autoimmune diseases. However, there are still avenues to explore, such as allostery for the development of drugs in the field of anxiety depression, bipolarity in particular. Other concepts are suggested in this article as the β-arrestins potential therapeutic targets in Alzheimer's disease (AD), the inhibitors of phosphodiesterase 10A for Huntington's disease, and the epigenetic in schizophrenia, peroxisome proliferator-activated receptors in neurodegenerative diseases.

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Phosphodiesterase 10A inhibitors: a 2009 – 2012 patent update

Abstract: Several compounds from various companies are currently undergoing clinical testing, dominated by compounds in clinical Phase I. Focus is mainly on CNS diseases and schizophrenia is the leading target indication.

Cited by 35 publications

References 29 publications

Effect of chronic antipsychotic treatment on striatal phosphodiesterase 10A levels: a [11C]MP-10 PET rodent imaging study with ex vivo confirmation

Effect of chronic antipsychotic treatment on striatal phosphodiesterase 10A levels: a [11C]MP-10 PET rodent imaging study with ex vivo confirmation

TAK-063, a phosphodiesterase 10A inhibitor, modulates neuronal activity in various brain regions in phMRI and EEG studies with and without ketamine challenge

The Contribution of Aluminium to Alzheimer�s disease: A Neuropathological Investigation of Renal Dialysis Cases

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