Identification of the First PPARα/γ Dual Agonist Able to Bind to Canonical and Alternate Sites of PPARγ and to Inhibit its Cdk5-Mediated Phosphorylation.

08:00 EDT 10th September 2018 | BioPortfolio

Summary of "Identification of the First PPARα/γ Dual Agonist Able to Bind to Canonical and Alternate Sites of PPARγ and to Inhibit its Cdk5-Mediated Phosphorylation."

A new series of derivatives of the PPARα/γ dual agonist 1 allowed to identify the ligand (S)-6 as a potent partial agonist of both PPARα and γ subtypes. X-ray studies in PPARγ revealed two different binding modes of (S)-6 to canonical site. However, (S)-6 was also able to bind an alternate site as demonstrated by transactivation assay in the presence of a canonical PPARγ antagonist and supported from docking experiments. This compound did not activate the PPARγ-dependent program of adipocyte differentiation inducing a very less severe lipid accumulation compared to rosiglitazone, but increased the insulin-stimulated glucose uptake in 3T3-L1 adipocytes. Finally, (S)-6 inhibited the Cdk5-mediated phosphorylation of PPARγ at serine 273 that is currently considered the mechanism by which some PPARγ partial agonists exert antidiabetic effects similar to thiazolidinediones, without showing their typical side effects. This is the first PPARα/γ dual agonist reported to show this inhibitory effect representing the potential lead of a new class of drugs for treatment of dyslipidemic type 2 diabetes.


Journal Details

This article was published in the following journal.

Name: Journal of medicinal chemistry
ISSN: 1520-4804


DeepDyve research library

PubMed Articles [8988 Associated PubMed Articles listed on BioPortfolio]

Discovery of first-in-class thiazole-based dual FFA1/PPARδ agonists as potential anti-diabetic agents.

The free fatty acid receptor 1 (FFA1 or GPR40) and peroxisome proliferator-activated receptor δ (PPARδ) have attracted a lot of attention due to their role in promoting insulin secretion and sensibi...

Di-n-butyl phthalate modifies PMA-induced macrophage differentiation of THP-1 monocytes via PPARγ.

The present study examined effects of di-butyl phthalate (DBP) on phorbol myristate acetate (PMA)-induced macrophage differentiation of THP-1 monocytes, determined by morphological classification and ...

Design, synthesis, and biological evaluation of novel pan agonists of FFA1, PPARγ and PPARδ.

The free fatty acid receptor 1 (FFA1) and peroxisome proliferator-activated receptors (PPARs) have attracted interest as potent targets for the treatment of metabolic syndrome such as type 2 diabetes....

Identification of novel PPARα/γ dual agonists by pharmacophore screening, docking analysis, ADMET prediction and molecular dynamics simulations.

PPARα and PPARγ play an important role in regulating glucose and lipid metabolism. The single and selective PPARα or PPARγ agonists have caused several side effects such as edema, weight gain and ...

Discovery of potent and selective PPARα/δ dual antagonists and initial biological studies.

We previously published on the design and synthesis of novel, potent and selective PPARα antagonists suitable for either i.p. or oral in vivo administration for the potential treatment of cancer. Des...

Clinical Trials [2730 Associated Clinical Trials listed on BioPortfolio]

Peroxisome Proliferator-Activated Receptor-Gamma (PPAR-Gamma) Agonist in Diabetic End-Stage Renal Disease Patients

To test the hypothesis that PPAR-gamma agonist, rosiglitazone, induces carotid plaque regression in diabetic ESRD patients on maintenance PD via its anti-inflammatory property.

Effect of a PPAR-Alpha Agonist on the Age Related Changes in Myocardial Metabolism and Mechanical Function

The purpose of this study is to determine if treatment with a drug called fenofibrate, which is a PPAR-alpha agonist and controls how the heart metabolizes fats, will reverse the age-relat...

BezafibrateTreatment for Bipolar Depression: A Proof of Concept Study

We propose to test the hypothesis that bezafibrate, a pan-PPAR agonist, may be effective and safe for bipolar depression with the following specific aims: Aim #1. Proof-of-Concept Safety ...

Regulation of Lipoprotein Transport in Metabolic Syndrome

The purpose of this study is to determine whether PPAR-delta agonist (GW5015156)had favorable effect on lipoprotein metabolism.

Pilot Studies of Novel Therapies to Treat Resistant Focal Segmental Glomerulosclerosis (FSGS)

The current management of primary FSGS is predicated on the assumption that the disease is caused by an immune-mediated disturbance in glomerular barrier function. Therefore, most treatmen...

Medical and Biotech [MESH] Definitions

One of the PPAR nuclear transcription factors.

Wnt proteins are a large family of secreted glycoproteins that play essential roles in EMBRYONIC AND FETAL DEVELOPMENT, and tissue maintenance. They bind to FRIZZLED RECEPTORS and act as PARACRINE PROTEIN FACTORS to initiate a variety of SIGNAL TRANSDUCTION PATHWAYS. The canonical Wnt signaling pathway stabilizes the transcriptional coactivator BETA CATENIN.

A structurally diverse group of compounds distinguished from ESTROGENS by their ability to bind and activate ESTROGEN RECEPTORS but act as either an agonist or antagonist depending on the tissue type and hormonal milieu. They are classified as either first generation because they demonstrate estrogen agonist properties in the ENDOMETRIUM or second generation based on their patterns of tissue specificity. (Horm Res 1997;48:155-63)

A dual specificity phosphatase subtype that plays a role in intracellular signal transduction by inactivating MITOGEN-ACTIVATED PROTEIN KINASES. It has specificity for EXTRACELLULAR SIGNAL-REGULATED MAP KINASES.

A dual specificity phosphatase subtype that plays a role in intracellular signal transduction by inactivating MITOGEN-ACTIVATED PROTEIN KINASES. It has specificity for EXTRACELLULAR SIGNAL-REGULATED MAP KINASES and is primarily localized to the CYTOSOL.

Quick Search


DeepDyve research library

Relevant Topics

Radiology is the branch of medicine that studies imaging of the body; X-ray (basic, angiography, barium swallows), ultrasound, MRI, CT and PET. These imaging techniques can be used to diagnose, but also to treat a range of conditions, by allowing visuali...

An assay is an analytic procedure for qualitatively assessing or quantitatively measuring the presence or amount or the functional activity of a target entity.  This can be a drug or biochemical substance or a cell in an organism or organic sample. ...

Searches Linking to this Article