Discovery of novel 2-(4-aryl-2-methylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3β inhibitors

Kohara, Toshiyuki; Nakayama, Kazuki; Watanabe, Kazutoshi; Kusaka, Shin‐ichi; Sakai, Daiki; Tanaka, Hiroshi; Fukunaga, Kenji; Sunada, Shinji; Nabeno, Mika; Saitô, Kenichi; Eguchi, Junichi; Mori, Akiko; Tanaka, Shinji; Bessho, Tomoko; Takiguchi-Hayashi, Keiko; Horikawa, Takashi

doi:10.1016/j.bmcl.2017.06.077

Cited by 8 publications

(6 citation statements)

References 5 publications

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“…To better understand the improved potency of the pyrimidine-based hinge-binding heterocycle compared to the pyridine-based hinge binder, a torsional scan was conducted to probe the energetic profile of rotation about the bond between the aryl hinge-binder group and the amide bond. 68 Model substructures of the pyridine (50) and pyrimidine (51) chemotypes shown in Figure 4 were manually created in Maestro and minimized. The torsion (noted in red in Figure 4) was constrained at values from −150 to 180°in 30°i ncrements.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…A wide variety of structurally diverse classes of small-molecule GSK-3 inhibitors have been reported and are the subject of several recent review articles. ,,− Compounds with chemical structures, such as paullones, maleimides, − benzofurans, 2-aminopyrazines, 4-pyrimidinones, − 4-pyridinones, and indazoles − are among the classes of compounds that have been investigated as GSK-3 inhibitors for Alzheimer’s disease. More recently, a series of highly potent, selective, brain-penetrant oxazole-4-carboxamide GSK-3β inhibitors were discovered with the aid of structure-guided design and positron emission tomography (PET) imaging. , It was also found that lead radiolabeled analogues from this series may be suitable as GSK-3 PET imaging agents. , Encouraging results from experiments in animal models provide additional support for GSK-3 inhibition as a potential therapeutic approach for the treatment of Alzheimer’s disease.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of 2-(Anilino)pyrimidine-4-carboxamides as Highly Potent, Selective, and Orally Active Glycogen Synthase Kinase-3 (GSK-3) Inhibitors

Hartz,

Ahuja,

Luo

et al. 2023

J. Med. Chem.

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Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that serves as an important regulator of a broad range of cellular functions. It has been linked to Alzheimer’s disease as well as various other diseases, including mood disorders, type 2 diabetes, and cancer. There is considerable evidence indicating that GSK-3β in the central nervous system plays a role in the production of abnormal, hyperphosphorylated, microtubule-associated tau protein found in neurofibrillary tangles associated with Alzheimer’s disease. A series of analogues containing a pyrimidine-based hinge-binding heterocycle was synthesized and evaluated, leading to the identification of highly potent GSK-3 inhibitors with excellent kinase selectivity. Further evaluation of 34 and 40 in vivo demonstrated that these compounds are orally bioavailable, brain-penetrant GSK-3 inhibitors that lowered levels of phosphorylated tau in a triple-transgenic mouse Alzheimer’s disease model.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery of 2-(Anilino)pyrimidine-4-carboxamides as Highly Potent, Selective, and Orally Active Glycogen Synthase Kinase-3 (GSK-3) Inhibitors

Hartz,

Ahuja,

Luo

et al. 2023

J. Med. Chem.

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show abstract

“…Co-crystallization of GSK-3β with an inhibitor PF-04802367 revealed that the inhibitor binds at the ATP site of GSK-3β, where the triazole ring of PF-04802367 forms a strong π–cation interaction with Arg141 essential to its potency and selectivity − Virtual screening and molecular docking also led to identification of GSK-3β inhibitors containing isoquinoline and quinazolinone scaffolds that favor π–cation interactions with Arg141 at the ATP site of GSK-3β . Benzothiazinones are allosteric modulators of GSK-3β showing π–cation interactions with Lys205 .…”

Section: Inhibitor–enzyme Interactionsmentioning

confidence: 99%

π–Cation Interactions in Molecular Recognition: Perspectives on Pharmaceuticals and Pesticides

Liang

2018

J. Agric. Food Chem.

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The π-cation interaction that differs from the cation-π interaction is a valuable concept in molecular design of pharmaceuticals and pesticides. In this Perspective we present an up-to-date review (from 1995 to 2017) on bioactive molecules involving π-cation interactions with the recognition site, and categorize into systems of inhibitor-enzyme, ligand-receptor, ligand-transporter, and hapten-antibody. The concept of π-cation interactions offers use of π systems in a small molecule to enhance the binding affinity, specificity, selectivity, lipophilicity, bioavailability, and metabolic stability, which are physiochemical features desired for drugs and pesticides.

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“…RNA interference silencing of the GSK3β isoform has been effective in lowering phosphotau and improving function in mice tauopathy models [54,55]. New inhibitors including AZD1080, BTA-EG 4 and compounds based on 2-(4-aryl-2-methylpiperazin-1-yl)-pyrimidin-4-ones are under evaluation [56][57][58] and if successful, they could enter clinical trials of tauopathies, including PSP.…”

Section: Gsk3 Inhibitors Gsk3 Is the Main Enzyme That Phos-mentioning

confidence: 99%

Preclinical, phase I, and phase II investigational clinical trials for treatment of progressive supranuclear palsy

Shoeibi

Olfati

Litvan

2018

Expert Opinion on Investigational Drugs

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Our understanding of the pathological basis of progressive supranuclear palsy (PSP), as the most common atypical parkinsonian syndrome, has greatly increased in recent years and a number of disease-modifying therapies are under evaluation as a result of these advances. Areas covered: In this review, we discuss disease-modifying therapeutic options which are currently under evaluation or have been evaluated in preclinical or clinical trials based on their targeted pathophysiologic process. The pathophysiologic mechanisms are broadly divided into three main categories: genetic mechanisms, abnormal post-translational modifications of tau protein, and transcellular tau spread. Expert opinion: Once the best therapeutic approaches are identified, it is likely that some combination of interventions will need to be evaluated, but this will take time. It is critical to treat patients at early stages, and development of the Movement Disorder Society PSP diagnostic criteria is an important step in this direction. In addition, development of biological biomarkers such as tau PET and further refinement of tau ligands may help both diagnose early and measure disease progression. In the meantime, a comprehensive, personalized interdisciplinary approach to this disease is absolutely necessary.

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Discovery of novel 2-(4-aryl-2-methylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3β inhibitors

Cited by 8 publications

References 5 publications

Discovery of 2-(Anilino)pyrimidine-4-carboxamides as Highly Potent, Selective, and Orally Active Glycogen Synthase Kinase-3 (GSK-3) Inhibitors

Discovery of 2-(Anilino)pyrimidine-4-carboxamides as Highly Potent, Selective, and Orally Active Glycogen Synthase Kinase-3 (GSK-3) Inhibitors

π–Cation Interactions in Molecular Recognition: Perspectives on Pharmaceuticals and Pesticides

Preclinical, phase I, and phase II investigational clinical trials for treatment of progressive supranuclear palsy

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