Peroxisome Proliferator-Activated Receptor a. Agonists

Peroxisomes are intracellular cytoplasmic organelles and the major sites for enzymatic oxidation, including that of fatty acids. The proliferation of peroxisomes is stimulated by free fatty acids and some metabolites of arachidonic acid, which are ligands for nuclear receptor proteins, the PPARs. These, in turn, are a family of 

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Drew, B.G. and Calkin, A.C. (2007) Drug evaluation K-lll, an insulin-sensitizing peroxisome proliferators activated receptor a agonist. Current Opinion in Investigational Drugs, 8, 324—330. 

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. 

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. 

Burris TP, Pelton PD, Zhou L, et al. A novel method for analysis of nuclear receptor function at natural promoters peroxisome proliferator-activated receptor y agonist actions on a P2 gene expression detected using branched DNA messenger RNA quantitation. Mol Endocrinol 1999 13 410—417. 

Kozak KR, Gupta RA, Moody JS, Ji C, Boeglin WE, DuBois RN, Brash AR, Mamett LJ (2002b) 15-Lipoxygenase metabolism of 2-arachidonylglycerol. Generation of a peroxisome proliferator-activated receptor alpha agonist. J Biol Chem 277 23278-23286... 

Henke, B. Peroxisome proliferator-activated receptor a/ y dual agonists for the treatment of type 2 diabetes. J. Med. Chem. 2004, 47, 4118 127. 

Anderson, S. R, Howroyd, P., Liu, J., Qian, X., Bahnemann, R., Swanson, C., Kwak, M. K., Kensler, T. W., and Corton, J. C. (2004b). The transcriptional response to a peroxisome proliferator-activated receptor alpha agonist includes increased expression of proteome maintenance genes. J Biot Chem 279, 52390-52398. 

Grey, A., Bolland, M., Gamble, G. et al. (2007) The peroxisome proliferator-activated receptor y agonist rosiglitazone decreases bone formation and bone mineral density in healthy postmenopausal women a randomized,... 

A peroxisome proliferator-activated receptor a/y dual agonist with a unique in vitro profile and potent glucose and lipid effects in rodent models of type 2 diabetes and dyslipidemia. Molecular Endocrinology, 19, 1593-1605. 

Design and synthesis of N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl] methyljglycine [muraglitazar/BMS-298585], a movel peroxisome proliferator-activated receptor a/y dual agonist with efficacious glucose and lipid-lowering activities. Journal of Medicinal Chemistry, 48, 2248-2250. 

Etgen, G.J., Oldham, B.A., Johnson, W.T. et al. (2002) A tailored therapy for the metabolic syndrome the dual peroxisome proliferator-activate receptor-a/y agonist LY465608 ameliorates insulin resistance and diabetic hyperglycemia while improving cardiovascular risk factors in predinical models. Diabetes, 51, 1083-1087. 

Marrapodi, M. and J.Y. Chiang (2000). Peroxisome proliferator-activated receptor a (PPARoi) and agonist inhibit cholesterol 7a-hydroxylase gene (CYP7A1) transcription. J. Lipid Res. 41, 514-520. 

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... 

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. 

Hong, J.T., Lee, M.K., Park, K.S., Jung, K.M., Lee, R.D., Jung, H.K., Park, K.L, Yang, K.J. Chung, Y.S. (2002) Inhibitory effect of peroxisome proliferator-activated receptor gamma agonist on ochratoxin A-induced cytotoxicity and activation of transcription factors in cultured rat embryonic midbrain cells. J. Toxicol. Environ. Health A 65, 407—418. 

Compound (/t)-K-13675 (1, (R)-2-[3-(benzoxazol-2-yl)[3-(4-methoxyphenoxy) propyl] amino)methyl)phenoxy]butanoic acid) is a member of the class of peroxisome proliferator-activated receptor a (PPARa) agonists. 

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