Design and synthesis of 7-hydroxy-1H-benzoimidazole derivatives as novel inhibitors of glycogen synthase kinase-3β

Shin, Dayeon; Lee, Seung−Chul; Heo, Yong‐Seok; Lee, Woon-Young; Cho, Yong‐Soon; Kim, Yong Eun; Hyun, Young-Lan; Cho, Joong Myung; Lee, Yoon Sup; Ro, Seonggu

doi:10.1016/j.bmcl.2007.07.056

Cited by 42 publications

(19 citation statements)

References 11 publications

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“…Shin et al 68 reported new analogs of 7-hydroxy-1 H -benzimidazole as novel ATP-competitive GSK-3β inhibitors. Some of these inhibitors (Table 2 ) exhibited IC 50 values in the nanomolar (nM) range.…”

Section: Atp-competitive Gsk-3 Inhibitorsmentioning

confidence: 99%

Glycogen Synthase Kinase-3 (GSK-3)-Targeted Therapy and Imaging

Pandey¹,

DeGrado²

2016

Theranostics

143

119

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Glycogen synthase kinase-3 (GSK-3) is associated with various key biological processes, including glucose regulation, apoptosis, protein synthesis, cell signaling, cellular transport, gene transcription, proliferation, and intracellular communication. Accordingly, GSK-3 has been implicated in a wide variety of diseases and specifically targeted for both therapeutic and imaging applications by a large number of academic laboratories and pharmaceutical companies. Here, we review the structure, function, expression levels, and ligand-binding properties of GSK-3 and its connection to various diseases. A selected list of highly potent GSK-3 inhibitors, with IC50 <20 nM for adenosine triphosphate (ATP)-competitive inhibitors and IC50 <5 μM for non-ATP-competitive inhibitors, were analyzed for structure activity relationships. Furthermore, ubiquitous expression of GSK-3 and its possible impact on therapy and imaging are also highlighted. Finally, a rational perspective and possible route to selective and effective GSK-3 inhibitors is discussed.

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Section: Atp-competitive Gsk-3 Inhibitorsmentioning

confidence: 99%

Glycogen Synthase Kinase-3 (GSK-3)-Targeted Therapy and Imaging

Pandey¹,

DeGrado²

2016

Theranostics

143

119

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“…Of these, maleimides were some of the earliest GSK3 inhibitors with SB-216763 and SB-415286 GSK3: a therapeutic target for diabetes 892 GV Rayasam et al inhibiting GSK3a and GSK3b with Ki of 9 and 31 nmol·L -1 (Coghlan et al, 2000;MacAulay et al, 2003).These compounds stimulate glycogen synthesis in human liver cells and also induce expression of b catenin -LEF/TCF reporter gene (Coghlan et al, 2000). Arylmaleimide (Smith et al, 2001), pyrazolo pyridines (Witherington et al, 2003;Engler et al, 2005), pyrimidin amines (Tavares et al, 2004), series of pyrazolo arylhydrazones (Peat et al, 2004), thiazolo [5,4-f] quinazolin-9-ones (Testard et al, 2006), 7-hydroxy-1Hbenzoimidazole derivatives (Shin et al, 2007), bis(indolyl)maleimide pyridinophanes (Zhang et al, 2007) and pyrimidine derivatives (Miyazaki et al, 2008) have all been reported as potent and selective GSK3 inhibitors with some reported to have cellular efficacy. Of these 2-cyanoethylalsterpaullones are most potent with IC50s in picomolar range (Kunick et al, 2005).…”

Section: Gsk 3 Inhibitors For Type II Diabetesmentioning

confidence: 99%

Glycogen synthase kinase 3: more than a namesake

Rayasam¹,

Tulasi²,

Sodhi³

et al. 2009

British J Pharmacology

412

349

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Glycogen synthase kinase 3 (GSK3), a constitutively acting multi-functional serine threonine kinase is involved in diverse physiological pathways ranging from metabolism, cell cycle, gene expression, development and oncogenesis to neuroprotection. These diverse multiple functions attributed to GSK3 can be explained by variety of substrates like glycogen synthase, t protein and b catenin that are phosphorylated leading to their inactivation. GSK3 has been implicated in various diseases such as diabetes, inflammation, cancer, Alzheimer's and bipolar disorder. GSK3 negatively regulates insulin-mediated glycogen synthesis and glucose homeostasis, and increased expression and activity of GSK3 has been reported in type II diabetics and obese animal models. Consequently, inhibitors of GSK3 have been demonstrated to have anti-diabetic effects in vitro and in animal models. However, inhibition of GSK3 poses a challenge as achieving selectivity of an over achieving kinase involved in various pathways with multiple substrates may lead to side effects and toxicity. The primary concern is developing inhibitors of GSK3 that are anti-diabetic but do not lead to up-regulation of oncogenes. The focus of this review is the recent advances and the challenges surrounding GSK3 as an anti-diabetic therapeutic target.

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“…There are neither in vivo assays nor selectivity data published for these potential metal chelators 131–134 (Table 15(a)). However, compound 134 (GSK-3 β IC 50 = 15 nM) was cocrystallized with GSK-3 β (Figure 16) [134]. …”

Section: Small-molecule Inhibitors Of Glycogen Synthase Kinasementioning

confidence: 99%

Small-Molecule Inhibitors of GSK-3: Structural Insights and Their Application to Alzheimer's Disease Models

Krämer

Schmidt

Monte

2012

International Journal of Alzheimer's Disease

100

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The world health organization (WHO) estimated that 18 million people are struck by Alzheimer's disease (AD). The USA, France, Germany, and other countries launched major programmes targeting the identification of risk factors, the improvement of caretaking, and fundamental research aiming to postpone the onset of AD. The glycogen synthase kinase 3 (GSK-3) is implicated in multiple cellular processes and has been linked to the pathogenesis of several diseases including diabetes mellitus, cancer, and AD. Inhibition of GSK-3 leads to neuroprotective effects, decreased β-amyloid production, and a reduction in tau hyperphosphorylation, which are all associated with AD. Various classes of small molecule GSK-3 inhibitors have been published in patents and original publications. Herein, we present a comprehensive summary of small molecules reported to interact with GSK-3. We illustrate the interactions of the inhibitors with the active site. Furthermore, we refer to the biological characterisation in terms of activity and selectivity for GSK-3, elucidate in vivo studies and pre-/clinical trials.

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Design and synthesis of 7-hydroxy-1H-benzoimidazole derivatives as novel inhibitors of glycogen synthase kinase-3β

Cited by 42 publications

References 11 publications

Glycogen Synthase Kinase-3 (GSK-3)-Targeted Therapy and Imaging

Glycogen Synthase Kinase-3 (GSK-3)-Targeted Therapy and Imaging

Glycogen synthase kinase 3: more than a namesake

Small-Molecule Inhibitors of GSK-3: Structural Insights and Their Application to Alzheimer's Disease Models

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