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

Usui, Yoshihiro; Uehara, Fumiaki; Hiki, Shinsuke; Watanabe, Kazutoshi; Tanaka, Hiroshi; Shouda, Aya; Yokoshima, Satoshi; Aritomo, Keiichi; Adachi, Takashi; Fukunaga, Kenji; Sunada, Shinji; Nabeno, Mika; Saitô, Kenichi; Eguchi, Junichi; Yamagami, Keiji; Asano, Shouichi; Tanaka, Shinji; Yuki, Satoshi; Yoshii, Narihiko; Fujimura, Masatake; Horikawa, Takashi

doi:10.1016/j.bmcl.2017.06.078

Cited by 12 publications

(5 citation statements)

References 20 publications

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“…The most potent derivatives in vitro, compounds 7 and 8 (Figure 12), displayed very similar interactions with the GSK-3 active site, similar to the observed for compound tofacitinib, specifically with the residues Asp133, Val135, and Gln185 [85]. Identical methodologies were carried out by other researchers, in some cases employing molecular dynamics simulations, to assess the binding poses and affinities towards the GSK-3 active site for several compounds: derivatives with a 2-phenylmorpholine scaffold (PDB#3F88) [86], rosmarinic acid (PDB#1PYX) [87], indirubin (PDB#1I09) [88], and pyridinylimidazoles (PDB#4PTC) [89] as shown in Figure 12. On the other hand, Lozinskaya and co-workers studied the affinity of oxindole derivatives by molecular docking but targeting the ATP-binding site of GSK-3 (PDB#4J1R) to identify potential new allosteric GSK-3 inhibitors [90] (Figure 13).…”

Section: Glycogen Synthase Kinase-3supporting

confidence: 54%

Recent Developments in New Therapeutic Agents against Alzheimer and Parkinson Diseases: In-Silico Approaches

et al. 2021

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Neurodegenerative diseases (ND), including Alzheimer’s (AD) and Parkinson’s Disease (PD), are becoming increasingly more common and are recognized as a social problem in modern societies. These disorders are characterized by a progressive neurodegeneration and are considered one of the main causes of disability and mortality worldwide. Currently, there is no existing cure for AD nor PD and the clinically used drugs aim only at symptomatic relief, and are not capable of stopping neurodegeneration. Over the last years, several drug candidates reached clinical trials phases, but they were suspended, mainly because of the unsatisfactory pharmacological benefits. Recently, the number of compounds developed using in silico approaches has been increasing at a promising rate, mainly evaluating the affinity for several macromolecular targets and applying filters to exclude compounds with potentially unfavorable pharmacokinetics. Thus, in this review, an overview of the current therapeutics in use for these two ND, the main targets in drug development, and the primary studies published in the last five years that used in silico approaches to design novel drug candidates for AD and PD treatment will be presented. In addition, future perspectives for the treatment of these ND will also be briefly discussed.

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Section: Glycogen Synthase Kinase-3supporting

confidence: 54%

Recent Developments in New Therapeutic Agents against Alzheimer and Parkinson Diseases: In-Silico Approaches

et al. 2021

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“…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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“…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%

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

Cited by 12 publications

References 20 publications

Recent Developments in New Therapeutic Agents against Alzheimer and Parkinson Diseases: In-Silico Approaches

Recent Developments in New Therapeutic Agents against Alzheimer and Parkinson Diseases: In-Silico Approaches

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

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

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