PPAR-y receptor

Oxazolyl derivatives containing 1,2,4-oxadiazolyl-, 1,3,4-thiadiazolyl-, and 1,3,4-oxadiazolyl substituents, (I), were prepared by Cobb (1) and were effective as PPAR-y receptor antagonist and used in the treatment of diabetes, obesity, and metabolic syndrome disorders. 

To date, the major treatments for NAFLD have been those aimed at lowering body weight and fat content. Loss of weight is often associated with decreased ALT values in one study, a 1% decrease in weight was associated with an 8% decrease in ALT activity. The association of NAFLD with insulin resistance has suggested treatment with antidiabetic medications, particularly those that increase insulin responsiveness (such as PPAR-y receptor agonists and metformin), but there are no conclusive studies that document safety and efficacy. 

The PPAR-y receptor belongs to a family of nuclear receptors. When activated, these receptors translocate to the nucleus where they regulate the transcription of genes encoding proteins involved in the metabolism of carbohydrate and lipids. The answer is (D). 

Fig. 1. Mechanism of the pleiotropic actions of the thiazolidinediones. Working via the PPAR-y receptor system in adipose tissue, the thiazolidinediones interrupt the pathogenic signaling between the expanded visceral adipose mass in obesity, which leads to improved insulin sensitivity in skeletal muscle and hver, enhanced pancreatic P-cell insulin secretion, and improved vascular endothelial function. The processes affected by the thiazolidinediones include redistribution of adipose stores, reduced circulating levels of FFA, diminished levels and tissue effects of cytokines (TNF-a), and increased circulating levels of the insulin-sensitizing, anti-atherogenic plasma protein adiponectin, which also arises from adipose tissue. The thiazohdinediones have also been shown to have direct effects in muscle and endothelial cells, which is likely to also contribute to some of their pharmacologic activity.

Heart failure in those taking thiazolidine-diones has been explained by fluid retention in susceptible individuals PPAR-y receptors are present in the distal renal tubule collecting ducts [87 ]. 

The thiazolidinediones have also been reported to act as inhibitors of the respiratory chain at high concentrations, and this appears to account for their ability to activate AMGPK in cultured cells. However, the primary target of the thiazolidinediones appears to be the peroxisome proliferator-activated receptor-y ( PPAR-y), a member of the nuclear receptor superfamily expressed in adipocytes. One of the major effects of stimulation of PPAR-y in adipocytes is the release ofthe... 

A peroxisome proliferator-activated receptor (PPAR) binding site was identified in the murine FATP1 promoter. Several reports have shown a positive regulation of mouse FATPs by ligands that activate PPAR-a, PPAR-y, or PPAR-y/RXR heterodimers. 

NSAID use is also implicated in disease flares in patients with UC. NSAIDs may affect production of both nuclear factor kP and peroxisome proliferator activated receptors (e.g., PPAR-y), both of which are involved in regulating the intestinal responses.11... 

Thiazolidinediones are known to increase insulin sensitivity by stimulating peroxisome proliferator-activated receptor gamma (PPAR-y). Stimulation of PPAR-y results in a number of intracellular and extracellular changes, including an increased number of insulin receptors, increased insulin receptor sensitivity, decreased plasma fatty acid levels, and an increase in a host of intracellular signaling proteins that enhance glucose uptake. 

Burgermeister, E., Schnoebelen, A., Flament, A., Benz, J., Stihle, M., Gsell, B., Rufer, A., Ruf, A., Kuhn, B., Marki, H. P., Mizrahi, J., Sebokova, E., et al. (2006). A novel agonist of peroxiome proliferator-activated receptor-y (PPAR y) recruits PPAR y-coactivator-la, prevents triglyceride accumulation, and potentiates insuling signalling in vitro. Mol. Endocrinol. 20, 809-830. 

Ajulemic acid (77) Cannabinoid CP 7075 (IP 751, ajulemic acid, CT-3) (synthetic version) Neurological (neuropathic pain) Suppresses IL-lp and mahix metalloproteinases (MMPs) through a peroxisome proliferator-activated receptor (PPAR) y-mediated mechanism Phase I Cervelo Pharmaceuticals 615-618... 

C) Thiazolidinediones bind a nuclear receptor in tissue termed PPAR-y, which augments the expression of insulin-regulated genes. 

Netoglitazone is an insulin sensitizer currently in Phase II clinical trials. It is able to modulate both PPAR-a and PPAR-y subtypes of peroxisome proliferator-activated receptor (Phase ll). Metaglidasen (MBX-102) is the (—)-enantiomer of the NSAID halofenate. This selective PPAR-y nuclear receptor agonist is being evaluated (Phase II) as an insulin sensitizer. It is structurally different from the currently marketed glitazones (Figure 8.84). ... 

Thiazolidinediones stimulate certain peroxisome proliferator-activatedreceptors (PPAR-y). PPAR-y is a nuclear receptor and, through a series of events, increases cellular production of insulin-dependent enzymes. This is an example of upregulation. The cell is then more sensitive to the decreased insulin levels found in a person with type 2 diabetes. The two thiazolidinediones currently on the market are rosiglitazone (Avandia, A.73) and... 

While the thiazolidindiones enhance insulin-mediated glucose transport via binding to the peroxisome proliferator-activating receptor (PPAR-y), the presence of this receptor in vascular smooth muscle cells, inflammatory cells, and endothelial cells likely facilitates the drug s ability to inhibit vascular smooth muscle cell proliferation, reduce inflammation, improve dyslipidemia, and, by extension, reduce in-stent restenosis. 

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR)y AGONISTS FOR DIABETES... 

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