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PPAR Agonists,Compounds,Pharmaceutical Compositions,and Methods of Use Thereof

Journal:
ACS Medicinal Chemistry Letters


Issue Date:
2016


Abstract(summary):

Peroxisome proliferator-activated receptors (PPAR) are a family of nuclear receptor proteins. Their primary function is to act as transcription factors that regulate gene expression. To date, three major subtypes have been identified, PPAR alpha, PPAR delta, and PPAR gamma. These proteins are key regulators of major metabolic pathways such as fatty acid oxidation, lipogenesis, and carbohydrate utilization. Functionally, PPARs form heterodimers with retinoic acid receptors (RXR), and these heterodimers interact with PPAR receptor elements (PPRE) in DNA to form active transcriptional complexes. PPARa is highly expressed in the liver where it plays a key role in regulating lipid metabolism. PPAR gamma, however, is found primarily in adipose tissues where it regulates adipogenesis and carbohydrate metabolism. Finally, PPAR delta is widely expressed and has been detected in many areas of the body including the small intestine, colon, heart, spleen, liver, skeletal muscle, thymus, lung, and brain. PPAR delta's major function is the regulation of lipid and glucose metabolism. It was recently discovered that mice that are PPAR delta deficient exhibit abnormal neurophysiological processes. Specifically, these mice have substantially decreased myelination of nerve cells and increased inflammatory responses. These findings suggest that PPAR delta modulation may be a viable approach to the treatment of demyelinating diseases such as multiple sclerosis. The present disclosure describes compounds capable of modulating PPAR delta activity that are useful for the treatment of demyelinating and muscular diseases.


Page:
824---825


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