Hit Optimization of 5-Substituted-<i>N</i>-(piperidin-4-ylmethyl)-1<i>H</i>-indazole-3-carboxamides: Potent Glycogen Synthase Kinase-3 (GSK-3) Inhibitors with in Vivo Activity in Model of Mood Disorders

Furlotti, Guido; Alisi, Maria Alessandra; Cazzolla, Nicola; Dragone, Patrizia; Durando, L.; Magarò, Gabriele; Mancini, Francesca; Mangano, Giorgina; Ombrato, Rosella; Vitiello, Marco; Armirotti, Andrea; Capurro, Valeria; Lanfranco, Massimiliano; Ottonello, Giuliana; Summa, Maria; Reggiani, Angelo

doi:10.1021/acs.jmedchem.5b01208

Cited by 37 publications

(33 citation statements)

References 43 publications

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“…In this regard the neuroprotective action of lithium is well documented, so that the challenge for future is the development of promising new drugs based on GSK3 inhibition which are disease specific, have an improved safety and tolerability profile and produce an ameliorative effect on illness pathogenic mechanisms 49). Based on this rationale novel compounds have been discovered which can potentially lead to new avenues in the treatment of BD and provide cures for the illness and its many comorbidities 50). The test for the coming era is to continue endeavors in this regard so that new therapeutic agents can be brought into clinical practice for a recalcitrant disease.…”

Section: Main Subjectsmentioning

confidence: 99%

Wnt and GSK3 Signaling Pathways in Bipolar Disorder: Clinical and Therapeutic Implications

Muneer

2017

Clin Psychopharmacol Neurosci

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The neurobiology of bipolar disorder, a chronic and systemic ailment is not completely understood. The bipolar phenotype manifests in myriad ways, and psychopharmacological agents like lithium have long term beneficial effects. The enzyme glycogen synthase kinase 3 (GSK3) has come into focus, as lithium and several other mood stabilizing medications inhibit its activity. This kinase and its key upstream modulator, Wnt are dysregulated in mood disorders and there is a growing impetus to delineate the chief substrates involved in the development of these illnesses. In May 2016, a comprehensive literature search was undertaken which revealed that there is over activity of GSK3 in bipolar disorder with deleterious downstream effects like proinflammatory status, increased oxidative stress, and circadian dysregulation leading to declining neurotrophic support and enhanced apoptosis of neural elements. By developing specific GSK3 inhibitors the progressive worsening in bipolar disorder can be forestalled with improved prospects for the sufferers.

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Section: Main Subjectsmentioning

confidence: 99%

Wnt and GSK3 Signaling Pathways in Bipolar Disorder: Clinical and Therapeutic Implications

Muneer

2017

Clin Psychopharmacol Neurosci

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“…Indazole 12 showed good preliminary pharmacokinetic profile in vivo and showed a complete reversal of amphetamine hypermotility in a mouse model that mimics the hyperactivity component of bipolar disorder. [107], [108] Very recently a family of pyrazolodihydropyridine was discovered from a high throughput screening (HTS) against GSK-3 with nanomolar activity binding at the ATP pocket. [109] Drug development efforts resulted in compound 13 that has an enhanced specificity among 311 kinases, improved stability, induces myeloid differentiation and neurogenesis and is a potential drug candidate for the treatment of neurological disorders.…”

Section: Combinations Of Known Drugs With Gsk-3 Inhibitorsmentioning

confidence: 99%

Glycogen synthase kinase 3 (GSK-3) inhibitors: a patent update (2014-2015)

Palomo

Martı́nez

2016

Expert Opinion on Therapeutic Patents

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Glycogen synthase kinase (GSK-3) is a serine/threonine kinase that phosphorylates more than one hundred different sequences within proteins in a variety of different pathways. It is a key component of a remarkably large number of cellular processes and diseases. Imbalance of GSK-3 activity is involved in various prevalent pathological diseases, such as diabetes, neurodegenerative diseases and cancer. Understanding its role in different disorders has been central in the last several decades and there has been a significantly large development of GSK-3 inhibitors, some of which, show promising results for the treatment of these devastating diseases. Areas covered: This review covers patent literature on GSK-3 inhibitors and their applications published and/or granted between 2014 and 2015. Expert opinion: GSK-3 inhibitors have gained a prominent role in regenerative medicine based in their ability to modulate stem cells. Moreover, some allosteric modulators of GSK-3 emerge as safe compounds for chronic treatments.

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“…GSK-3beta is a serine/threonine protein kinase with high concentration in the brain, where it modulates gene expression and neural plasticity among other neurodevelopment processes (Frame and Cohen 2001;Furlotti, et al 2015). Recent studies suggest that the inhibition of GSK3beta through the increase of serine phosphorylation modulates the pharmacological response and reduces observable hyperactive behavior in this model.…”

Section: Animal Modelsmentioning

confidence: 99%

An overview of mice models: a key for understanding subtypes of mania

Arias

Zuluaga

Jaramilo

2016

Int. j. psychol. res.

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Animal models have been broadly used in the study of pathophysiology and molecular and neurochemical pathways in neuropsychiatric diseases. Different approaches have used both consanguineous and non-consanguineous mice models to model behavioral patterns associated with the maniac spectrum. However, the disadvantages of validating clinical and experimental protocols have hindered the replication of these studies. In this article, the advantages and disadvantages of using consanguineous lines and non-consanguineous stocks in mice animal models for the study of mania and its subtypes are discussed. Additionally, new experimental alternatives to advance the pathogenesis and pharmacogenetics of mania using animal models are proposed and analyzed RESUMENPalabras clave: modelos animales, trastorno afectivo bipolar, knockout y manía.Los modelos animales se han utilizado ampliamente en el estudio de la fisiopatología y vías moleculares y neuroquímicos en enfermedades neuropsiquiátricas. Diferentes enfoques han utilizado modelos de ratones consanguíneos y no consanguíneos para modelar patrones de comportamiento asociados con el espectro maníaco. Sin embargo, las desventajas de la validación de los protocolos clínicos y experimentales han obstaculizado la replicación de estos estudios. En este artículo, se discuten las ventajas y desventajas del uso de líneas consanguíneas y no consanguíneas en modelos animales de ratones para el estudio de la manía y sus subtipos. Además, se proponen y analizan las nuevas alternativas experimentales para avanzar en la patogénesis y la farmacogenética de la manía utilizando modelos animales.R e v i e w

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Hit Optimization of 5-Substituted-N-(piperidin-4-ylmethyl)-1H-indazole-3-carboxamides: Potent Glycogen Synthase Kinase-3 (GSK-3) Inhibitors with in Vivo Activity in Model of Mood Disorders

Cited by 37 publications

References 43 publications

Wnt and GSK3 Signaling Pathways in Bipolar Disorder: Clinical and Therapeutic Implications

Wnt and GSK3 Signaling Pathways in Bipolar Disorder: Clinical and Therapeutic Implications

Glycogen synthase kinase 3 (GSK-3) inhibitors: a patent update (2014-2015)

An overview of mice models: a key for understanding subtypes of mania

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