Novel triazines as potent and selective phosphodiesterase 10A inhibitors

Malamas, Michael S.; Stange, Hans; Schindler, R; Lankau, Hans‐Joachim; Grunwald, Christian; Langen, Barbara; Egerland, Ute; Hage, Thorsten; Ni, Yi; Erdei, James; Fan, Kristi; Parris, Kevin; Marquis, Karen L.; Grauer, Steve; Brennan, Julie; Navarra, Rachel; Graf, Radka; Harrison, Boyd L.; Robichaud, Albert J.; Kronbach, Thomas; Pangalos, Menelas N.; Brandon, Nicholas J.; Hoefgen, Norbert

doi:10.1016/j.bmcl.2012.07.076

Cited by 22 publications

(12 citation statements)

References 22 publications

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“…Hyperactivity induced by MK‐801, an N ‐methyl‐ D ‐aspartate receptor (NMDAR) antagonist, is used as a model for acute psychosis based on the NMDAR hypofunction hypothesis of schizophrenia and is often applied to evaluate the antipsychotic‐like effects of PDE10A inhibitors in rodents . TAK‐063 (0.3 mg/kg p.o.)…”

Section: General Pharmacological Characterization Of Tak‐063mentioning

confidence: 99%

“…Hyperactivity induced by MK-801, an N-methyl-D -aspartate receptor (NMDAR) antagonist, is used as a model for acute psychosis based on the NMDAR hypofunction hypothesis of schizophrenia 47 and is often applied to evaluate the antipsychotic-like effects of PDE10A inhibitors in rodents. 48,49 TAK-063 (0.3 mg/kg p.o.) produced >70% suppression of MK-801-induced hyperactivity in mice and rats at doses that resulted in 26% and 38% PDE10A occupancy, respectively ( Figure 1E,F).…”

Section: General Pharmacological Characterization Of Tak-063mentioning

confidence: 99%

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TAK‐063, a novel PDE10A inhibitor with balanced activation of direct and indirect pathways, provides a unique opportunity for the treatment of schizophrenia

Suzuki

Kimura

2018

CNS Neurosci Ther

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The basal ganglia regulates motor, cognitive, and emotional behaviors. Dysfunction of dopamine system in this area is implicated in the pathophysiology of schizophrenia characterized by positive symptoms, negative symptoms, and cognitive deficits. Medium spiny neurons (MSNs) are principal output neurons of striatum in the basal ganglia. Similar to current antipsychotics with dopamine D receptor antagonism or partial agonism, phosphodiesterase 10A (PDE10A) inhibitors activate indirect pathway MSNs, leading to the expectation of therapeutic potential for the treatment of psychosis. PDE10A inhibitors also activate direct pathway MSNs which may be associated with cognitive functions. These pathways have competing effects on antipsychotic-like activities and extrapyramidal symptoms in rodents. Therefore, careful consideration of activation pattern of these pathways by a PDE10A inhibitor is critical to produce potent efficacy and superior safety profiles. In this review, we outline the pharmacological profile of TAK-063, a novel PDE10A selective inhibitor. Our study revealed that off-rates of PDE10A inhibitors may characterize their pharmacological profiles via regulation of each MSN pathway. TAK-063, with a faster off-rate property, could provide a unique opportunity as a novel therapeutic approach to treatment of psychosis and cognitive deficits in schizophrenia. TAK-063 also has a therapeutic potential in other basal ganglia disorders.

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Section: General Pharmacological Characterization Of Tak‐063mentioning

confidence: 99%

Section: General Pharmacological Characterization Of Tak-063mentioning

confidence: 99%

TAK‐063, a novel PDE10A inhibitor with balanced activation of direct and indirect pathways, provides a unique opportunity for the treatment of schizophrenia

Suzuki

Kimura

2018

CNS Neurosci Ther

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“…In our continuous effort to develop fluorine-18 labeled PET tracers dedicated to molecular imaging of PDE2A, we selected the benzoimidazotriazine (BIT) scaffold (Figure 1) as lead structure by replacing the pyrido ring of the TA compounds with a benzo ring [26,27]. As a first result, we very recently reported on the synthesis and inhibitory potency of nine new fluorinated derivatives based on this BIT scaffold [28].…”

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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“…The phosphodiesterase 10A model was developed on the basis of the experimental structure of the enzyme (PDB ID: 3SNI) [ 43 ]. The structure was refined using default settings in the Protein Preparation Wizard.…”

Section: Methodsmentioning

confidence: 99%

Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives

et al. 2020

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In this study, a series of compounds derived from 4-methoxy-1H-isoindole-1,3(2H)-dione, potential ligands of phosphodiesterase 10A and serotonin receptors, were investigated as potential antipsychotics. A library of 4-methoxy-1H-isoindole-1,3(2H)-dione derivatives with various amine moieties was synthesized and examined for their phosphodiesterase 10A (PDE10A)-inhibiting properties and their 5-HT1A and 5-HT7 receptor affinities. Based on in vitro studies, the most potent compound, 18 (2-[4-(1H-benzimidazol-2-yl)butyl]-4-methoxy-1H-isoindole-1,3(2H)-dione), was selected and its safety in vitro was evaluated. In order to explain the binding mode of compound 18 in the active site of the PDE10A enzyme and describe the molecular interactions responsible for its inhibition, computer-aided docking studies were performed. The potential antipsychotic properties of compound 18 in a behavioral model of schizophrenia were also investigated.

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Novel triazines as potent and selective phosphodiesterase 10A inhibitors

Cited by 22 publications

References 22 publications

TAK‐063, a novel PDE10A inhibitor with balanced activation of direct and indirect pathways, provides a unique opportunity for the treatment of schizophrenia

TAK‐063, a novel PDE10A inhibitor with balanced activation of direct and indirect pathways, provides a unique opportunity for the treatment of schizophrenia

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 N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives

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