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Abstract Details
Discovery of novel modulators for the PPARa (peroxisome proliferator activated receptor a): Potential therapies for nonalcoholic fatty liver disease
Bioorg Med Chem. 2021 May 1;41:116193. doi: 10.1016/j.bmc.2021.116193. Online ahead of print.
Donna D Yu1, Gregg Van Citters2, Hongzhi Li3, Brian M Stoltz4, Barry M Forman3
Author information
1Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA; Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: ddyu7b@gmail.com.
2Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA. Electronic address: gregg.vancitters@vancittersquality.com.
3Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
4Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a severe liver disease causing serious liver complications, including nonalcoholic steatohepatitis (NASH). Nuclear receptor PPARα (peroxisome proliferator-activated receptor α) has drawn special attention recently as a potential developmental drug target to treat type-2 diabetes and related diseases due to its unique functions in regulating lipid metabolism, promoting triglyceride oxidation, and suppressing hepatic inflammation, raising interest in PPARα agonists as potential therapies for NAFLD. However, how PPARα coordinates potential treatment of NAFLD and NASH between various metabolic pathways is still obscure. Here, we show that the DY series of novel selective PPARα modulators activate PPARα by up-regulating PPARα target genes directly involved in NAFLD and NASH. The design, synthesis, docking studies, and in vitro and in vivo evaluation of the novel DY series of PPARα agonists are described.