Discovery of Pyridones As Oral AMPK Direct Activators

Mirguet, Olivier; Sautet, Stéphane; Clément, Catherine-Anne; Toum, Jérôme; Donche, Frédéric; Marques, Celine; Rondet, Emilie; Pizzonero, Mathieu; Beaufils, Benjamin; Dudit, Yann; Huet, Pascal; Trottet, Lionel; Grondin, Pascal; Brusq, Jean-Marie; Boursier, Eric; Saintillan, Yannick; Nicodème, Edwige

doi:10.1021/ml400157g

Cited by 13 publications

(16 citation statements)

References 17 publications

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“…175 The major goal of the GSK group was to improve oral absorption and the selectivity profile. Compound 17 is an AMPK activator that is selective for β1-containing heterotrimeric complexes with poor oral bioavailability.…”

Section: Direct Activatorsmentioning

confidence: 99%

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Small Molecule Adenosine 5′-Monophosphate Activated Protein Kinase (AMPK) Modulators and Human Diseases

2014

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Adenosine 5′-monophosphate activated protein kinase (AMPK) is a master sensor of cellular energy status that plays a key role in the regulation of whole-body energy homeostasis. AMPK is a serine/threonine kinase that is activated by upstream kinases LKB1, CaMKKβ and Tak1 among others. AMPK exists as αβγ trimeric complexes that are allosterically regulated by AMP, ADP and ATP. Dysregulation of AMPK has been implicated in a number of metabolic diseases including type 2 diabetes mellitus and obesity. Recent studies have associated roles of AMPK with the development of cancer and neurological conditions making it a potential therapeutic target to treat human diseases. This perspective focuses on the structure and function of AMPK, its role in human diseases and its direct substrates and provides a brief synopsis of key AMPK modulators and their relevance in human diseases.

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Section: Direct Activatorsmentioning

confidence: 99%

“…Several analogs in this series showed improved blood exposure when co-dosed with a P-glycoprotein (P-gp) inhibitor suggesting that they may susceptible to Pgp-mediated efflux. 175 …”

Section: Direct Activatorsmentioning

confidence: 99%

Small Molecule Adenosine 5′-Monophosphate Activated Protein Kinase (AMPK) Modulators and Human Diseases

2014

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“…Additionally, the chemical structure of gambogic acid seems to be lipophilic enough to penetrate the BBB. Nevertheless, its more lipophilic amide derivative (without the negative future science group Review Zaks, Getter & Gruzman [183] future science group Activators of AMPK: not just for Type II diabetes Review charge of the carboxylic acid moiety) is also active and has better chances to reach the brain [132]. The selectivity of the AMPK activators' antiproliferative or apoptotic effects in cancer cells is not yet fully understood.…”

Section: Cancermentioning

confidence: 99%

“…Orally active direct AMPK activators were designed and synthesized by Mirguet et al [183]. A new pyridone scaffold-based molecule shows oral activity in a reasonable therapeutic dose.…”

Section: Direct Activatorsmentioning

confidence: 99%

Activators of AMPK: Not Just for Type II Diabetes

2014

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Recent discoveries of AMPK activators point to the large number of therapeutic candidates that can be transformed to successful designs of novel drugs. AMPK is a universal energy sensor and influences almost all physiological processes in the cells. Thus, regulation of the cellular energy metabolism can be achieved in selective tissues via the artificial activation of AMPK by small molecules. Recently, special attention has been given to direct activators of AMPK that are regulated by several nonspecific upstream factors. The direct activation of AMPK, by definition, should lead to more specific biological activities and as a result minimize possible side effects.

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“…[6] Despite significant therapeutic interest in AMPK as a target [7] and intensive study of its activation mechanisms in the last decade, [6a,8] a limited number of effective approaches have been developed to the design of compounds that activate the kinase. [9] One can distinguish (1) targeting of AMP-binding sites, causing allosteric activation of AMPK; [10] (2) development of compounds targeted at an alternative allosteric site (so-called ADaM site), identified by high-throughput screening; [11] (3) blocking the function of the autoinhibitory domain (AID) of the kinase. [12] The use of the latter approach is complicated by the lack of complete data on the structure of AMPK.…”

Section: Introductionmentioning

confidence: 99%

Activating Effect of 3‐Benzylidene Oxindoles on AMPK: From Computer Simulation to High‐Content Screening

et al. 2020

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AMP‐activated protein kinase (AMPK) is currently the subject of intensive study and active discussions. AMPK performs its functions both at the cellular level, providing the switch between energy‐consuming and energy‐producing processes, and at the whole body level, particularly, regulating certain aspects of higher nervous activity and behavior. Control of such a ‘main switch’ compensates dysfunctions and associated diseases. In the present paper, we studied the binding of 3‐benzylidene oxindoles to the kinase domain of the AMPK α‐subunit, which is thought to prevent its interaction with the autoinhibitory domain and thus result in the AMPK activation. For this purpose, we developed the cellular test system based on the AMPKAR plasmid, which implements the FRET effect, synthesized a number of 3‐benzylidene oxindole compounds and simulated their binding to various sites of the kinase domain. The most probable binding site for the studied compounds was established by the correlation of calculated and experimental data. The obtained results allow to analyze various classes of AMPK activators using virtual and high‐content screening.

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Discovery of Pyridones As Oral AMPK Direct Activators

Cited by 13 publications

References 17 publications

Small Molecule Adenosine 5′-Monophosphate Activated Protein Kinase (AMPK) Modulators and Human Diseases

Small Molecule Adenosine 5′-Monophosphate Activated Protein Kinase (AMPK) Modulators and Human Diseases

Activators of AMPK: Not Just for Type II Diabetes

Activating Effect of 3‐Benzylidene Oxindoles on AMPK: From Computer Simulation to High‐Content Screening

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