Fibrate ligand

Fibrates function primarily as ligands for the nuclear transcription receptor, PPAR- . They transcriptionally up-regulate... 

Figure 7.12 show the results of a validation study. The task was to identify bioisosteric replacements for fragments in known PPAR (peroxisome pro-liferator-activated receptor) ligands. Fibrates are therapeutic agents for the treatment of metabolic disorders and activate PPARoc, a member of the PPAR family.It has been demonstrated that the 2-methyl-propionic acid moiety 7.6 is responsible for the selectivity of fibrates toward PPARa. SQUIRRELnovo suggests bioisosteric replacement for this group. These groups have been patented for action on PPARoc. ... 

A. Mechanism and Effects Fibric acid derivatives (eg, gemfibrozil, fenofibrate, clofibrate) are ligands for the peroxisome proliferator-activated receptor-alpha (PPAR-a) protein, a receptor that regulates transcription of genes involved in lipid metabolism. Tbis interaction with PPAR-a results in increased activity of lipoprotein lipase and enhanced clearance of triglyceride-rich lipoproteins (Figure 35-2). Cholesterol biosynthesis in the liver is seeondarily reduced. The fibrates reduce serum triglyceride concentrations (Table 35-3). There may be a small reduction in LDL cholesterol and a small increase in HDL levels. 

Both EPA and C14-S-acetic acid are converted to their respective CoA esters in mitochondria. Furthermore, in contrast to DHA-CoA, EPA-CoA and C14-S-acetyl-CoA are easily transferred into the mitochondria by the CAT system. EPA is more difficult to oxidize than saturated and monounsaturated fatty acids, due to the double bonds and C14-S-acetic acid is non-oxidizable by P-oxidation,due to the sulfur atom in 3-position. Thus, accumulation of their respective CoA esters in the mitochondria might give an fatty acid overload signal leading to inaeased mitochondrial fatty acid oxidation. C14-S-acetic acid mimics the effects of peroxisome proliferators such as the fibrates and it was recently shown that it may be a ligand for the peroxisome proliferating activated receptor (PPAR) a. As administration of the 3-thia fatty acids seem to force EPA to the mitochondria, an additional fish oil effect might be seen. 

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