6-Heteroaryl-pyrazolo[3,4-b]pyridines: potent and selective inhibitors of glycogen synthase kinase-3 (GSK-3)

Witherington, Jason; Bordas, Vincent; Gaiba, Alessandra; Naylor, A.; Rawlings, Anthony D.; Slingsby, Brian P.; Smith, David George Emslie; Takle, Andrew K.; Ward, Robert W.

doi:10.1016/s0960-894x(03)00646-2

Cited by 82 publications

(31 citation statements)

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“…12,13) Within this context and as part of a research program aimed to study modified purine analogues as potential protein kinase inhibitors, we have explored the pyrazolopyridine scaffold and present in this study the design, synthesis and evaluation of a number of new substituted pyrazolo [3,4-c] pyridines for inhibitory potency against a panel of eight protein kinases.…”

Section: )mentioning

confidence: 99%

“…10) Although a number of putative allosteric inhibitors appeared in the literature, 11) most of the reported GSK3 inhibitors are ATP competitive, and are often characterized by the presense of a central purine-like heterocyclic scaffold, substituted with a characteristic carboxamide residue. 12,13) Within this context and as part of a research program aimed to study modified purine analogues as potential protein kinase inhibitors, we have explored the pyrazolopyridine scaffold and present in this study the design, synthesis and evaluation of a number of new substituted pyrazolo [3,4-c] pyridines for inhibitory potency against a panel of eight protein kinases.…”

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confidence: 99%

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Synthesis, Docking Study and Kinase Inhibitory Activity of a Number of New Substituted Pyrazolo[3,4-<i>c</i>]pyridines

et al. 2017

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A series of new pyrazolo[3,4-c]pyridines bearing various 1, 3, 5 or 1, 3, 7 pattern substitutions, were designed and synthesized. Some of them showed interesting inhibitory activity mainly against glycogen synthase kinase 3 (GSK3)α/β as well as against cdc2-like kinases 1 (CLK1) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), with good selectivity and remarkable structure-activity relationships (SARs), without being cytotoxic. Molecular simulations in correlation with biological data revealed the importance of the existence of N1-H as well as the absence of a bulky 7-substituent.Key words pyrazolopyridine; kinase inhibition; glycogen synthase kinase 3 (GSK3)α/β; purine analogue; molecular simulation Neurodegenerative diseases are among the most challenging diseases with poorly known mechanism and lack of complete cure. Alzheimer's disease (AD) in particular, is the most prevalent cause of dementia, very devastating for the patients and their families, provided that current treatments offer only modest symptomatic relief. This severe mental disorder is mostly aging-associated and represents a global health problem, since it currently affects more than 30 million people worldwide, and its incidence is predicted to rise significantly, due to the increasing average life span. 1) In an effort to explain the pathogenesis of AD, many hypotheses have been explored, among them neurotransmitter modulation, chronic inflammation, metal-induced oxidative stress, elevated cholesterol, and glycogen synthase kinase 3 (GSK-3) implication are of major importance.2) GSK-3 is a ubiquitous serine/threonine kinase, which was first described as the major regulator of glycogen metabolism. It was revealed that GSK-3 plays central roles in important cell signaling pathways, and its malfunction is associated with neurodegeneration and the pathogenesis of several diseases, including diabetes type II, immune and bipolar disorders, chronic inflammation, heart failure and cancer.3) In AD, GSK-3 promotes neuronal death and is a linker between the two histopathological hallmarks: the deposition of extracellular senile plaques composed of amyloid-beta (Aβ) peptide, and the accumulation of hyperphosphorylated microtubule-binding tau protein, leading to tau aggregation and the formation of intracellular neurofibrillary tangles. 4)On the other hand, substantial evidence exists to support the involvement of additional phylogenetically and physiologically relevant protein kinases in neurodegenerative disorders, and, most notably, cyclin dependent kinase 5 (CDK5), 5) dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK 1A), 6) casein kinase 1 (CK1) 7) and cdc2-like kinases CLK1 and CLK2 8) are also investigated as potential targets for the development of novel AD therapeutics. Consequently, the exploitation of small molecule inhibitors for potential inhibitory activity against a set of the above mentioned protein kinases could offer interesting information and assist in the understanding of AD and related tau...

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confidence: 99%

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Synthesis, Docking Study and Kinase Inhibitory Activity of a Number of New Substituted Pyrazolo[3,4-<i>c</i>]pyridines

et al. 2017

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“…The 2,4,6-trimethylphenyl analogue, 36 (IC 50 : >1.0µM) resulted as a poor cdk2 inhibitor in contrast with 2,6-difluoro-4-methyl analogue, 37 (IC 50 : 0.009µM). 43 , (Figure 8) homologous to cdk2…”

Section: Effect Of 4-position Substitutionmentioning

confidence: 99%

“…SAR studies suggest that a broad range of substituents are tolerated at the O 6 -position, but none resulted in appreciable activity or specificity as seen with NU2058, which suggests that the hydrogen bonds formed by the substituents within the ribose pocket contributed greatly towards potency and selectivity. X-ray structure of NU2058 bound to monomeric cdk2 revealed that it forms a triplet of hydrogen bonds within the ATP binding site between residues in the hinge region of cdk2 and the NH 2 , N3, and N9 nitrogen atoms of the inhibitor 43 . Comparison of structures ( Figure 9) of NU2058 (pdb code: 1e1v) and olomoucine (pdb code: 1w0x) bound to monomeric cdk2 revealed that NU2058 represents a different class of inhibitor to olomoucine [15] (IC 50 : 7 µM) as the two compounds bind in different orientations 45 .…”

Section: Effect Of 6-position Substitution Gsk-3 Class Of Inhibitorsmentioning

confidence: 99%

Pyridines, pyridazines and guanines as CDK2 inhibitors: a review

Babu¹,

Narasu²,

Srinivas³

2007

Arkivoc

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Cell cycle progresses by the activation of cyclin and cdk complexes. They act as check points and regulate the transition of cell cycle from one phase to another. Cdk2 inhibitors decrease the kinase activities by blocking the transition from G1 to S phases. In this article, we present a review on purine based cdk2 inhibitors. The review covers in great detail the different structures and the effects on cdk2 inhibition by various substitutions. The substitutions that most greatly influence the orientation and binding towards the ATP binding site are discussed and the effects of several substituents that explored the active site region of cdk2 with bound inhibitor has provided a rationale to review four relatively new families of purine based cdk2 inhibitors such as imidazo[1,2-a]pyridines, imidazo[1,2-b]pyridazines, 1H-pyrazolo [3,4-b]pyridines and O 6 -substituted guanines, respectively. The orientation and hydrogen bond interactions of analogues with Leu83, Asp86 and Lys33 residues influence the binding and the major features responsible for effective cdk2 inhibitor discovery and design are presented.

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“…目前报道的 GSK-3 抑制剂按照作用机制分类主要包括 ATP 竞争性抑制剂、非 ATP 竞争性抑制剂、底物竞争性抑制剂、变构抑制剂、不可逆抑制剂和天然产物来源的 GSK-3 抑制剂. [22] 、Zhang [23] 、Olesen [24] 、Smith [25] 等课题组报道的一系列杂环化合物 5～9 是第二代 ATP 竞争性抑制剂, 相对于第一代抑制剂活性和选择性显著提高. 1,3,4-噁二唑 [26] (10)、苯并异吲哚-1,3-二酮 [27] Figure 4 Structures of isonicotinamide derivatives [34] .…”

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Novel Drug Development Process of Anti-Alzheimer Targeted to Glycogen Synthase Kinase-3

Zhao¹,

Sun²

2018

Chin. J. Org. Chem.

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6-Heteroaryl-pyrazolo[3,4-b]pyridines: potent and selective inhibitors of glycogen synthase kinase-3 (GSK-3)

Cited by 82 publications

References 16 publications

Synthesis, Docking Study and Kinase Inhibitory Activity of a Number of New Substituted Pyrazolo[3,4-<i>c</i>]pyridines

Synthesis, Docking Study and Kinase Inhibitory Activity of a Number of New Substituted Pyrazolo[3,4-<i>c</i>]pyridines

Pyridines, pyridazines and guanines as CDK2 inhibitors: a review

Novel Drug Development Process of Anti-Alzheimer Targeted to Glycogen Synthase Kinase-3

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