PPAR agonists

In humans, biomarker responses to PPAR agonists by and large support possible antiatherosclerotic benefits, although recent clinical trial results have not proven conclusive. Further large-scale trials should help define the role of PPAR agonist therapy on cardiovascular events in at-risk populations. 

Nadanadva, S. etal. (2007) Mitochondrial impairment by PPAR agonists and statins identified via immunocaptured OXPHOS complex activities and respiration. Toxicology and Applied Pharmacology,... 

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. 

Houpis, I.N., Patterson, L.E., Alt, C.A., Rizzo, J.R., Zhang, T.Y. and Haurez, M. S3mthesis of PPAR Agonist via Asymmetric Hydrogenation of a Cinnamic Acid derivative and Stereo-specific Displacement of (S)-2-Chloropropionic Acid. Org. Lett. 2005, 7, 1947-1950. 

For studying the side effect potential of candidate compounds on blood triglycerides and cholesterol as well as on metabolic rate, insulin sensitivity and body weight development multiple dose studies for at least 1 week are necessary. For transcriptional active compounds like the PPAR agonist (peroxisome... 

Oxazolyl-aryloxyacetic acid derivatives, (II), prepared by Brooks (2) were effective as PPAR agonists and used in treating diabetes, obesity, hyperglycemia, and hyperlipidemia. 

H. Song, K. Yan, X. Xu, and M. W. Lo, Quantitative determination of MK-0767, a dual alpha/gamma peroxisome prohferators-activated receptor (PPAR) agonist, in human plasma by liquid chromatography-tandem mass spectrometry, J. Chromatogr. B 810 (2004), 7-13. 

Figure 7.12 Bioisosteric replacement of 2-methylpropionic acid in 7.6. These fragments were suggested by SQUIRRELnovo based on shape matching (mesh) and pharmacophore point scoring (LIQUID fuzzy pharmacophore method). All bioisosteres have been proven to exhibit the desired bioactivity as building-blocks for PPAR agonists.

Fibric adds Clofibrate Gemfibrozil Fenofibrate Increase VLtt-catabolism PPAR , agonist LDLi 5-20% HDL t 10%-20% TG i 20%-S0% Gl upset, dyspepsia, gallstones, T LFTs, myopathy Nonmetabolism Warfarin Cyclosporine Statins Liver or severe renal disease primary biliary cirrhosis preexisting gallbladder disease... 

Significantly, PGC-la knockout mice also show lesions in the brain regions affected in Alzheimer s disease [106]. It should be noted that TZD agonists of PPARy have a number of effects on mitochondrial metabolism, many of which are receptor-independent actions of the drugs [108]. Roses et al. have postulated that the PPAR agonists act to improve mitochondrial function and... 

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. ... 

Figure 8-11 Structures of fenofibrate (43), FA (44), KCL (45), and designed PPAR agonists (46 and 47).

Chinetti-Gbaguidi, G., Fruchart, J.-C. and Staels, B. (2005) Therapeutical effects of PPAR agonists assessed by biomarker modulation. Biomarkers Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals, 10 (Suppl 1), S30. 

---