Peroxisome-proliferator-activated agonists

Thiazolidinediones (PPARy-agonists) Thiazolidine-diones ( pioglitazone, rosiglitazone) lower blood glucose levels in animal models of insulin resistance and also in insulin resistant patients. They are agonists of the peroxisome proliferator-activated receptor y (PPARy). Because they enhance the effect of insulin and reduce serum insulin levels in insulin resistant patients, thiazolidinediones are usually referred to as insulin sensitizers . 

HP-jS-CD were added. All compounds were resolved in 20 min (see Figure 5). The data indicated that the validated method offered equivalent and complementary information, in terms of selectivity, sensitivity, accuracy, linearity, and precision, to that of an established gradient LC method employed for similar purposes. Ragaglitazar is a dual peroxisome proliferator-activated receptor ot and y agonist intended to restore insulin sensitivity and correct diabetic dyslipidemia. A chiral CZE method combining two CDs, sulfobutylether-jS-CD and dimethyl-/i-CD, lent itself to the analysis of ragaglitazar, its distomer (the (+)... 

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

Several fluorine-containing drugs are currently in development for the treatment of diabetes. These are peroxisome proliferator-activated nuclear receptor (PPAR) agonists, aldose reductase, and dipeptidylpeptidase IV (DPP-IV) inhibitors. 

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). ... 

Mechanism of Action Potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPAR(gamma)) which decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. 

Philips J-C, Petite C, Willi J-P, Buchegger F, Meier CA. Effect of peroxisome proliferator-activated receptor 8 agonist rosiglitazone on dedifferentiated thyroid cancers. Nucl Med Comm 2004 25 1183-6. 

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. 

Sidhu JS, Cowan D, Kaski JC, The effects of Rosiglitazone, a peroxisome proliferator activated receptor gamma agonist, on markers of endothelial cell activation, C-reactive protein, and fibrinogen levels in non-diabetic coronary artery disease patients. J Am Coll Cardiol 2003 42 1757-1763. 

Heneka, M. T., Feinstein, D., Galea, E., Gleichmann, M., Wullner, U., and Klockgether, T. (1999). Peroxisome proliferator-activated receptor gamma agonists protect cerebellar granule cells from cytokine-induced apoptotic cell death by inhibition of inducible nitric oxide synthase. J. Neuroim-munol. 100, 156-168. 

Kielian, T., and Drew, P. D. (2003). Effects of peroxisome proliferator-activated receptor-gamma agonists on central nervous system inflammation. J. Neurosci. Res. 71, 315-325. 

Park, S. W., Yi, J. H., Miranpuri, G., Satriotomo, I., Bowen, K., Resnick, D. K., and Vemuganti, R. (2007). Thiazolidinedione class of peroxisome proliferator-activated receptor gamma agonists prevents neuronal damage, motor dysfunction, myelin loss, neuropathic pain, and inflammation after spinal cord injury in adult rats. J. Pharmacol. Exp. Ther. 320, 1002—1012. 

Polak, P. E., Kalinin, S., Dello Russo, C., Gavrilyuk, V., Sharp, A., Peters, J. M., Richardson, J., Willson, T. M., Weinberg, G., and Feinstein, D. L. (2005). Protective effects of a peroxisome proliferator-activated receptor-beta/delta agonist in experimental autoimmune encephalomyelitis. J. Neuroimmunol. 168, 65—75. 

II. Mechanism of Action of Peroxisome Proliferator-Activated Receptort Agonists... 

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR AGONISTS FOR DIABETES 183... 

Buckingham, R. E., Al-Barazanji, K. A., Toseland, C. 1). N. el al. (1998). Peroxisome Proliferator-Activated Receptor-y Agonist, Rosiglitazone, Protects Against Nephropathy and Pancreatic Islet Abnormalities in Zucker Fatty Rrts. Diabetes 47, 1326-1334. 

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