Peroxisome proliferator-activated receptor PPAR agonists

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) AGONISTS FOR TYPE 2... 

Thiazolidinediones are another class of heterocyclic carboxylic acid surrogates commonly used for peroxisome proliferator-activated receptors (PPAR) agonists, as potent antihyperglycemic and lipid activity modulators. Other interesting, but less studied heterocyclic surrogates are 3,5-dioxo-l,2,4-oxadiazohdine, 3-hydroxy-1,2,5-thiadiazoles, l,2,4-oxadiazole-5(4//)-ones, 1,2,4-thiadi-azole-5(4H)-ones , 3,5-difluoro-4-hydroxyphenyl, and 3 -hydroxy-7-pyrones. ... 

As proof of principle, there are several reports of studies in rodents where the object has been to characterise the toxic effects of specific chemicals on the liver or kidneys. Distinct protein patterns have been associated with exposure to peroxisome proliferators activated receptor (PPAR) agonists and non-steroidal anti-inflammatory dmgs that can be used to screen new chemical entities for activity (Anderson et ak, 1996 Eberini et ak, 1999). Proteomics identified the relationship between changes in the expression of a... 

Synthetic peroxisome proliferator-activated receptors (PPARs) agonist in clinical use such as thiazolidinediones (TZDs) may limit inflammatory response (194). Also, PPARy, but not PPARa, activators repress interferon-y-induced MHC-II expression and subsequent inhibition of T-lymphocyte activation in atheroma-associated cells (195). 

The fibrates are another class of antihyperlipidemic drug and are frequently coadministered with a statin. Fibrates act as agonists of the peroxisome proliferator-activated receptors (PPAR), particularly PPAR-a. PPARs are nuclear receptors that influence gene expression and lipid metabolism. Examples of fibrates include gemfibrozil (Lopid, A.110) and fenofibrate (Tricor, A.lll) (Figure A.30). Fenofibrate is hydrolyzed in the body to its active form, fenofibric acid (A.112). Fibrates do not decrease LDL levels as effectively as statins, but fibrates do elevate HDL cholesterol levels. 

Statins, used predominantly in the treatment of hypercholesterolemia, act by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which regulates the synthesis of cholesterol. Statins are also agonists of peroxisome proliferator activated receptors (PPARs), which are part of the nuclear receptor superfamily and when activated, can suppress transcription of pro-inflammatory genes (Chinetti et al., 2000). In vitro and in vivo studies have shown that a decrease in serum cholesterol inhibits the production of beta amyloid and plaque (Simons et al., 1998 Fassbender et al.,... 

The activation of the retinoid X receptor, which dimerizes with peroxisome proliferator-activated receptors (PPARs), leads to an enhanced clearance of A(f from the brain of a transgenic mouse model of AD, with increased expression of ApoE and its main transporters. Both a PPARy agonist (ciplitazone) and a PPARa agonist (WT 14.643) are able to protect neurons by modulating mitochondrial fusion and fission, leading to a better response of neurons to oxidative stress, suggesting that a PPAR-based therapy could act simultaneously in different cellular components [437]. 

Peroxisome proliferator-activated receptor (PPAR) y and PPARra agonists modulate mitochondrial fusion-fission dynamics Relevance to reactive oxygen species (ROS)-related neurodegenerative disorders PLoS One 8 e64019. doi 10.1371/journal.pone. 0064019... 

Kasuga, J., Yamasaki, D., Araya, Y, Nakagawa, A., Makishima, M., Doi, T., Hashimoto, Y, Miyachi, H. Design, synthesis, and evaluation of a novel series of alpha-substituted phenylpropanoic acid derivatives as human peroxisome proliferator-activated receptor (PPAR) alpha/ delta dual agonists for the treatment of metabolic syndrome. Bioorg. Med. Chem. 2006, 14, 8405-8414. 

Since then, approximately 70 studies have been reported in the literature, and far more have been conducted internally within pharmaceutical companies, documenting the effectiveness of cTn as a biomarker to identify, assess, and monitor preclinical cardiac toxicity (O Brien 2008). This has been demonstrated for several classes of drugs, including adrenergic agents, agonists of peroxisome proliferator-activated receptors (PPAR especially for alpha-PPARs), anthracyclines and other anticancer drugs, and phosphodiesterase inhibitors. 

Improvement of insulin action in T2D subjects must therefore be a primary aim for the normalisation of blood glucose values, mainly in the postprandial state. Normalisation of insulin sensitivity in peripheral tissues in T2D has, however, never been the main objective, as we possessed no tools carrying the potential for reaching this objective. However, the recently discovered PPAR (peroxisome proliferator-activated receptor) gamma agonists, namely gUtazones, carry this potential. 

The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. The three PPAR isoforms (a, p/8, and y) are known to occur in mammalian tissues. In response to specific agonists, these receptors form dimers and translocate to the nucleus, where they act as agonist-dependent transcription factors and regulate gene... 

---