Synthesis, in vitro and in silico studies of a PPARγ and GLUT-4 modulator with hypoglycemic effect

Navarrete‐Vázquez, Gabriel; Torres‐Gómez, Héctor; Hidalgo-Figueroa, Sergio; Ramírez-Espinosa, Juan José; Estrada-Soto, Samuel; Medina-Franco, José L.; León‐Rivera, Ismael; Alarcón-Aguilar, Francisco Javier; Almanza-Perez, Julio César

doi:10.1016/j.bmcl.2014.07.068

Cited by 24 publications

(16 citation statements)

References 22 publications

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“…Our data also suggest that compounds 2 and 3 induces GLUT-4 expression in the same way than pioglitazone does. Several evidences indicate that increased levels of GLUT-4 expression in skeletal muscle are critical for the regulation of glucose homeostasis [ 7 , 17 , 26 ].…”

Section: Resultsmentioning

confidence: 99%

“…Compounds 1 – 3 were the most active against some of targets identified as key elements in diabetes in this work, and they were chosen in order to assess their in vivo activity over Streptozotocin (STZ) and Nicotinamide (NA) diabetic induced mice, a well-known non-insulin-dependent diabetes murine model [ 7 , 17 ]. Glibenclamide was used as a positive control, in order to ensure that the damage over β-cells was partial and mice pancreas still produces insulin, that responds to a secretagogue such as sulfonylurea drug used in this work.…”

Section: Resultsmentioning

confidence: 99%

“…An alternative mechanism for the control of glucose levels refers to the peroxisome proliferator-activated receptors (PPARs) action. PPARs, members of the nuclear hormone receptor family, occur in three subtypes: PPARα, PPARγ, and PPARβ/δ [ 7 ]. Each subtype regulates tissue-specific target genes acting as lipid sensors and regulators of glucose homeostasis, such as the solute carrier family 2 (facilitated glucose transporter), member 4 (GLUT-4) [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis and in Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic Acids

et al. 2018

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We have synthesized a small series of five 3-[4-arylmethoxy)phenyl]propanoic acids employing an easy and short synthetic pathway. The compounds were tested in vitro against a set of four protein targets identified as key elements in diabetes: G protein-coupled receptor 40 (GPR40), aldose reductase (AKR1B1), peroxisome proliferator-activated receptor gama (PPARγ) and solute carrier family 2 (facilitated glucose transporter), member 4 (GLUT-4). Compound 1 displayed an EC50 value of 0.075 μM against GPR40 and was an AKR1B1 inhibitor, showing IC50 = 7.4 μM. Compounds 2 and 3 act as slightly AKR1B1 inhibitors, potent GPR40 agonists and showed an increase of 2 to 4-times in the mRNA expression of PPARγ, as well as the GLUT-4 levels. Docking studies were conducted in order to explain the polypharmacological mode of action and the interaction binding mode of the most active molecules on these targets, showing several coincidences with co-crystal ligands. Compounds 1–3 were tested in vivo at an explorative 100 mg/kg dose, being 2 and 3 orally actives, reducing glucose levels in a non-insulin-dependent diabetes mice model. Compounds 2 and 3 displayed robust in vitro potency and in vivo efficacy, and could be considered as promising multitarget antidiabetic candidates. This is the first report of a single molecule with these four polypharmacological target action.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis and in Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic Acids

et al. 2018

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“…An established pharmacophore of dual PPAR agonists consists of an acidic head group, a central aromatic ring, and an additional lipophilic substituent connected to the aromatic ring by a flexible linker. 22 It is well-established that PPAR ligands should be able to adopt a conformation wrapped around helix 3. 23 We investigated the differences between 8c and 8d considering the conformational space.…”

Section: Resultsmentioning

confidence: 99%

Design and synthesis of fused soluble epoxide hydrolase/peroxisome proliferator-activated receptor modulators

et al. 2016

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“…Several basic nitrogen compounds are associated with cardiovascular risks due to human ether-a-go-go related gene (hERG) channel blockade [18][19][20]. Compounds -showed low prediction of hERG channel blockage at clinically relevant concentrations ( < 10 M), being considered as potentially noncardiotoxic compounds.…”

Section: In Silico Toxicitymentioning

confidence: 99%

Synthesis and In Vitro AMPK Activation of Cycloalkyl/Alkarylbiguanides with Robust In Vivo Antihyperglycemic Action

Gutiérrez-Lara

Martínez-Conde

Rosales-Ortega

et al. 2017

Journal of Chemistry

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This work describes the design, synthesis in one step, and the in vitro, in vivo, and in silico antidiabetic evaluation of a series of ten alicyclic and aromatic (alkyl +aryl: alkaryl)biguanides, analogues of metformin and phenformin. The design was conceived using isosteric replacement, chain-ring transformation, and lower and higher homologation strategies. All compounds were obtained as crystals and their structure was confirmed on the basis of their spectral data (NMR and mass spectra), and their purity was ascertained by microanalysis. Compounds were in vitro evaluated as activators of AMP-Activated Protein Kinase (AMPK). The results indicated that compounds , , and showed similar or even better effect compared to metformin. Docking analysis was performed with regulatory subunit of AMPK, showing several interactions with nucleotide binding pocket. The in vivo evaluation of compounds -at a single dose of 50 mg/kg was performed in a murine experimental model of diabetes. The results showed an important and robust decrease of plasmatic glucose levels (−40%). Compound was selected for an oral glucose tolerance test, showing an antihyperglycemic effect similar to metformin. The in vivo results indicated that compounds -may be effective in treating experimental T2DM.

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Synthesis, in vitro and in silico studies of a PPARγ and GLUT-4 modulator with hypoglycemic effect

Cited by 24 publications

References 22 publications

Design, Synthesis and in Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic Acids

Design, Synthesis and in Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic Acids

Design and synthesis of fused soluble epoxide hydrolase/peroxisome proliferator-activated receptor modulators

Synthesis and In Vitro AMPK Activation of Cycloalkyl/Alkarylbiguanides with Robust In Vivo Antihyperglycemic Action

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