PPAR-a agonist

Current evidence suggests that PPAR activation may limit inflammation and hence atherosclerosis. Both PPAR-a and PPAR-y can reduce T-cell activation, as shown by decreased production of EFN-y. PPAR-a agonists also rqness endothelial VCAM-1 expression and inhibit the inflammatory activation of vascular SMCs, while PPAR-y agonists repress endothelial chemokine expression and decrease macrophage MMP production. 

Nagata, K., Noda, A., Ichihara, G., Yamada, A., Kato, T. et al. (2006) Attenuation of cardiac dysfunction by a PPAR-a agonist is associated with down-regulation of redox-regulated transcription factors. Journal of Molecular and Cellular Cardiology, 41, 318-329. 

Nissen, S.E., Nicholls, S.J., Wolski, K., Howey, D.C., McErlean, E., Wang, M..-D., Gomez, E.V. and Russo, J.M. (2007) Effects of a potent and selective PPAR-a agonist in patients with atherogenic dyslipidemia or hypercholesterolemia. Journal of the American Medical Association, 297, 1362-1373. 

Since almost all of the long-chain PFCs tested are PPAR-a agonists and/or induce xenobiotic-metabolizing enzymes in the liver, PFCs may be expected to induce some or all of the neoplastic effects seen with PFOA in rodents. There is currently insufficient information to definitively classify long-chain PFCs as human carcinogens. More complete characterization of their mechanisms of action in humans versus rodents will be necessary in order to determine whether this class of compounds poses a carcinogenic hazard to humans at current cumulative levels of exposure. 

Xu X. et al., 2005. Quantitative determination of a novel dual PPAR aly agonist using online turbulent flow extraction with liquid chromatography-tandem mass spectrometry. J Chromatogr B 814 29. 

Larsen, T. M., Toubro, S., and Astrup, A. (2003). PPAR gamma agonists in the treatment of type II diabetes Is increased fatness commensurate with long-term efficacy Int. ]. Obesity 27,147-161. 

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). ... 

Hypolipoproteinemia is likely to be a rare adverse effect. The measurement of HDL cholesterol and triglycerides before and after staring thiazolidinedione therapy will allow its detection. On withdrawing therapy concentrations return to normal. This effect may be specific to rosiglitazone, as it is becoming apparent that the PPAR-y agonists vary in their effects. 

Xu, X., Yana, K. X., Songa, H., and Loa, M. W. (2005a). Quantitative determination of a novel dual PPAR a/y agonist using on-line turbulent-flow extraction with liquid chromatography-tandem mass spectrometry. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 814 29-36. 

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. 

Jiang, C., Ting, A. T., and Seed, B. (1998) PPAR-Gamma Agonists Inhibit Production of Monocyte Inflammatory Cytokines. Nature 391, 82-86. 

Vinyl A-(2-benzoylphenyl)-L tyrosine derivatives, (V), prepared by Jeppesen (5) were partial PPAR-a, PPAR-y, and PPAR-8 agonists and used in treating obesity, hyperglycemia, hyperlipidemia, and hypercholesterolemia. 

Fig. 1.2. The SMRT peptide binds as an extended helix and interacts with helix-12 (magenta) of PPAR-a, which is in a much different conformation than it is in an agonist structure. From PDB entry 1 KKQ.

Fig. 1.30 Interactions of the PPAR-a/ co-agonist with PPAR-. The Y-shape of the ligand is complementary to the Y-shape of the ligand binding pocket. One of the three arms of the...

Fig. 1.31 Key polar interactions of PPAR-a/y co-agonist AZ-242 with PPAR-(...

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