Discovery of novel modulators for the PPARα (peroxisome proliferator activated receptor α): Potential therapies for nonalcoholic fatty liver disease

Donna D Yu; Gregg Van Citters; Hongzhi Li; Brian M Stoltz; Barry M Forman

doi:10.1016/j.bmc.2021.116193

Discovery of novel modulators for the PPARα (peroxisome proliferator activated receptor α): Potential therapies for nonalcoholic fatty liver disease

Bioorg Med Chem. 2021 Jul 1:41:116193. doi: 10.1016/j.bmc.2021.116193. Epub 2021 May 1.

Authors

Donna D Yu¹, Gregg Van Citters², Hongzhi Li³, Brian M Stoltz⁴, Barry M Forman³

Affiliations

¹ Department 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.
² Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA. Electronic address: gregg.vancitters@vancittersquality.com.
³ Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
⁴ Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.

PMID: 34022528
DOI: 10.1016/j.bmc.2021.116193

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.

Keywords: Hepatic steatohepatitis; NAFLD; NASH; PPARα; Selective PPARα agonists.

MeSH terms

Animals
Diet, High-Fat / adverse effects*
Female
Gene Expression Regulation / drug effects
Homeostasis
Lipid Metabolism
Mice
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease / chemically induced*
Non-alcoholic Fatty Liver Disease / drug therapy*
PPAR alpha / agonists*
Up-Regulation

Substances

PPAR alpha