Synthesis and structure–activity relationships of fibrate-based analogues inside PPARs

Giampietro, Letizia; D’Angelo, Alessandra; Giancristofaro, Antonella; Ammazzalorso, Alessandra; Filippis, Barbara De; Fantacuzzi, Marialuigia; Linciano, Pasquale; Maccallini, Cristina; Amoroso, Rosa

doi:10.1016/j.bmcl.2012.09.111

Cited by 31 publications

(24 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The introduction of a diazenyl function spaced by a three atom linker from clofibric acid resulted in GL479, a good PPAR α/γ agonist (PPARα EC 50 = 0.6 µM, PPARγ EC 50 = 1.4 µM). GL479 was also able to influence the gene expression of CPT1A, an enzyme involved in lipid metabolism in liver, related with long-chain fatty acid transport into hepatocyte mitochondria (Giampietro et al, 2012). Our present crystallographic studies revealed that GL479 interacts with ligand binding pocket (LBP) of both PPARα and PPARγ but displays different binding modes.…”

Section: Introductionmentioning

confidence: 70%

“…GL479 and two other compounds, all synthesized and described by Giampietro et al (2012), share the same functional features, i. e. full agonist for the PPARα agonist and partial agonist for PPARγ. The unique difference among these compounds structure is the length of the linker between the aromatic lipophilic tail and the center (one, two or three carbons).…”

Section: Ppar Lbp Occupancy Versus Full/partial Agonismmentioning

confidence: 99%

“…Aiming to contribute to better understanding of a structural basis of full and partial activation of PPARs, here we present the structures of the ligand binding domain (LBD) of PPARα and PPARγ complexed with GL479, a PPARα/γ dual agonist ( Figure 1A). This compound was synthesized by Giampietro and colleagues in the search for novel PPAR ligands based on a combination of two key pharmacophores: the clofibric acid skeleton and natural products as stilbene, chalcone, and their bioisosters (Giampietro et al, 2012). The aim of this project was to improve the pharmacological activity of classical fibrates by introducing the antioxidant, antilipidemic and antiplatelet properties of natural scaffolds.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Different binding and recognition modes of GL479, a dual agonist of Peroxisome Proliferator-Activated Receptor α/γ

Santos

Bernardes

Giampietro

et al. 2015

Journal of Structural Biology

Self Cite

View full text Add to dashboard Cite

Section: Introductionmentioning

confidence: 70%

Section: Ppar Lbp Occupancy Versus Full/partial Agonismmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Different binding and recognition modes of GL479, a dual agonist of Peroxisome Proliferator-Activated Receptor α/γ

Santos

Bernardes

Giampietro

et al. 2015

Journal of Structural Biology

Self Cite

View full text Add to dashboard Cite

“…Importantly, the fenofibrates that are PPAR α agonists have not been shown to induce bladder cancer. PPAR α agonists with a different structure, the clofibrates [85], have been shown to weakly enhance BBN-induced bladder carcinogenesis [86]. However, a second report indicated that clofibrates are not carcinogenic [87].…”

Section: The Impact Of Dual-acting Ppar Agonistsmentioning

confidence: 99%

Deciphering the Roles of Thiazolidinediones and PPARγin Bladder Cancer

et al. 2017

View full text Add to dashboard Cite

The use of thiazolidinedione (TZD) therapy in type II diabetic patients has proven useful in the lowering of blood glucose levels. However, recent investigations have shown that there may be potential health concerns associated, including the risk of developing bladder cancer as well as complications in the cardiovasculature. TZDs are ligands for the nuclear receptor PPARγ, and activation causes lipid uptake and insulin sensitization, both of which are critical processes for diabetic patients whose bodies are unable to utilize insulin effectively. Several studies have shown that PPARγ/TZDs decrease IGF-1 levels and, thus, reduce cancer growth in carcinomas such as the pancreas, colon, liver, and prostate. However, other studies have shed light on the potential of the receptor as a biomarker for uroepithelial carcinomas, particularly due to its stimulatory effect on migration of bladder cancer cells. Furthermore, PPARγ may provide the tumor-promoting microenvironment by de novo synthesis of nutrients that are needed for bladder cancer development. In this review, we closely examine the TZD class of drugs and their effects on PPARγ in patient studies along with additional molecular factors that are positive modulators, such as protein phosphatase 5 (PP5), which may have considerable implications for bladder cancer therapy.

show abstract

“…Fibrates have a common structural feature containing a carboxylic head and hydrophobic tail linked by one or more aromatic rings as found in fenofibrate ( Fig. 1) 15 . The structural basis of the agonistic behavior of fibrates of PPARα has been established.…”

mentioning

confidence: 92%

Structural Basis for PPARα Activation by 1H-pyrazolo-[3,4-b]pyridine Derivatives

Yoshida

Oki

Doi

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Small-molecule agonism of peroxisome proliferator-activated receptor α (ppARα), a ligand-activated transcriptional factor involved in regulating fatty acid metabolism, is an important approach for treating dyslipidemia. Here, we determined the structures of the ligand-binding domain (LBD) of ppARα in complex with 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid derivatives, which were recently identified as PPARα-selective activators with markedly different structures from those of the wellknown ppARα agonists fibrates. The crystal structures of the complexes showed that they form a canonical hydrogen-bond network involving helix 12 in the LBD, which is thought to be essential for ppARα activation, as also observed for fibrates. However, the phenyl side chain of the compounds occupies a small cavity between Ile272 and Ile354, which is rarely accessed by fibrates. This unique feature may be essential for subtype selectivity and combine with the well-characterized binding mode of fibrates to improve activity. These findings demonstrate the advantage of using 1H-pyrazolo-[3,4-b] pyridine as a skeleton of PPARα agonists and provide insight into the design of molecules for treating dyslipidemia.

show abstract

Synthesis and structure–activity relationships of fibrate-based analogues inside PPARs

Cited by 31 publications

References 39 publications

Different binding and recognition modes of GL479, a dual agonist of Peroxisome Proliferator-Activated Receptor α/γ

Different binding and recognition modes of GL479, a dual agonist of Peroxisome Proliferator-Activated Receptor α/γ

Deciphering the Roles of Thiazolidinediones and PPARγin Bladder Cancer

Structural Basis for PPARα Activation by 1H-pyrazolo-[3,4-b]pyridine Derivatives

Contact Info

Product

Resources

About