Discovery of new acylaminopyridines as GSK-3 inhibitors by a structure guided in-depth exploration of chemical space around a pyrrolopyridinone core

Sivaprakasam, Prasanna; Han, Xiaojun; Civiello, Rita L.; Jacutin-Porte, Swanee; Kish, Kevin; Pokross, Matt; Lewis, H.A.; Ahmed, Nazia; Szapiel, Nicolas; Newitt, John A.; Baldwin, Eric T.; Xiao, Hong; Krause, Carol; Park, Hyunsoo; Nophsker, Michelle; Lippy, Jonathan; Burton, Catherine R.; Langley, David R.; Macor, John E.; Dubowchik, Gene M.

doi:10.1016/j.bmcl.2015.03.046

Cited by 81 publications

(71 citation statements)

References 30 publications

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“…Many of the GSK‐3β potent inhibitors were designed to compete with ATP active site and were derived from pyrrolopyridinone scaffold. Many of these inhibitors possess IC50s in the nanomolar range and were capable of reducing tau protein phosphorylation, e,g, pyridyl pyridine derivative, compound 32, Figure , with an IC 50 of 4.4 nM …”

Section: Future Directions For Alzheimer's Disease Treatmentmentioning

confidence: 99%

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

187

175

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Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no current cure. One of the important therapeutic approaches of AD is the inhibition of β‐site APP cleaving enzyme‐1 (BACE1), which is involved in the rate‐limiting step of the cleavage process of the amyloid precursor protein (APP) leading to the generation of the neurotoxic amyloid β (Aβ) protein after the γ‐secretase completes its function. The produced insoluble Aβ aggregates lead to plaques deposition and neurodegeneration. BACE1 is, therefore, one of the attractive targets for the treatment of AD. This approach led to the development of potent BACE1 inhibitors, many of which were advanced to late stages in clinical trials. Nonetheless, the high failure rate of lead drug candidates targeting BACE1 brought to the forefront the need for finding new targets to uncover the mystery behind AD. In this review, we aim to discuss the most promising classes of BACE1 inhibitors with a description and analysis of their pharmacodynamic and pharmacokinetic parameters, with more focus on the lead drug candidates that reached late stages of clinical trials, such as MK8931, AZD‐3293, JNJ‐54861911, E2609, and CNP520. In addition, the manuscript discusses the safety concerns and insignificant physiological effects, which were highlighted for the most successful BACE1 inhibitors. Furthermore, the review demonstrates with increasing evidence that despite tremendous efforts and promising results conceived with BACE1 inhibitors, the latest studies suggest that their clinical use for treating Alzheimer's disease should be reconsidered. Finally, the review sheds light on alternative therapeutic options for targeting AD.

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Section: Future Directions For Alzheimer's Disease Treatmentmentioning

confidence: 99%

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

187

175

View full text Add to dashboard Cite

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“…ATP‐competitive inhibitors for GSK‐3β have been discovered from different sources, including marine organisms (e.g., indirubin ( 42 ), Figure ) and its analogues with IC 50 values in the range of 5–50 n m , and hymenialdisine ( 43 , Figure ) with IC 50 =10 n m . Other notable examples include staurosporine ( 44 , Figure ) with IC 50 =3–7 n m , 3‐anilino‐4‐arylmaleimides ( 45 , Figure ) with IC 50 =20 n m , F389‐0663 ( 46 , Figure ) with IC 50 =1.6 μ m , compound 47 (Figure ) with IC 50 =2.19 μ m , and the potent pyrrolopyridinone scaffold ( 48 , Figure ) with IC 50 =0.29 n m …”

Section: Glycogen Synthase Kinase 3‐beta (Gsk‐3β)mentioning

confidence: 99%

“…[194] Other notable examples include staurosporine (44,F igure 5) with IC 50 = 3-7 nm, [195] 3-anilino-4-arylmaleimides (45,F igure 5) with IC 50 = 20 nm, [196] F389-0663 (46,F igure 5) with IC 50 = 1.6 mm, [197] compound 47 ( Figure 5) with IC 50 = 2.19 mm, [198] and the potent pyrrolopyridinone scaffold (48,Figure5)w ith IC 50 = 0.29 nm. [199] Also, AZD1080 (49,F igure 5) was able to reach clinical trials for AD. Initially,t his indolyl derivativep resenting a K i value of 6.9 nm,w as found to decrease tau protein hyperphosphoryla- www.chemmedchem.org tion in cell cultures and to restore synaptic plasticity in the brains of rats, but its progress was discontinued because of poor therapeutic performance andsafety concerns,possibly related to potent inhibition and ATP-competitiveness in its binding to GSK-3b.…”

Section: Glycogen Synthase Kinase 3-beta (Gsk-3b)mentioning

confidence: 99%

Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

et al. 2019

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Among neurodegenerative disorders, Alzheimer's disease (AD) is the most common type of dementia, and there is an urgent need to discover new and efficacious forms of treatment for it. Pathological patterns of AD include cholinergic dysfunction, increased β‐amyloid (Aβ) peptide concentration, the appearance of neurofibrillary tangles, among others, all of which are strongly associated with specific biological targets. Interactions observed between these targets and potential drug candidates in AD most often occur by competitive mechanisms driven by orthosteric ligands that sometimes result in the production of side effects. In this context, the allosteric mechanism represents a key strategy; this can be regarded as the selective modulation of such targets by allosteric modulators in an advantageous manner, as this may decrease the likelihood of side effects. The purpose of this review is to present an overview of compounds that act as allosteric modulators of the main biological targets related to AD.

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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.…”

mentioning

confidence: 99%

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

Sklepari

Lougiakis

Papastathopoulos

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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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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Discovery of new acylaminopyridines as GSK-3 inhibitors by a structure guided in-depth exploration of chemical space around a pyrrolopyridinone core

Cited by 81 publications

References 30 publications

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

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

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