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

• Published in: Bioorganic & medicinal chemistry Vol. 41; p. 116193
• Main Authors: Yu, Donna D., Van Citters, Gregg, Li, Hongzhi, Stoltz, Brian M., Forman, Barry M.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.07.2021; Elsevier
• Subjects: Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Hepatic steatohepatitis; Life Sciences & Biomedicine; NAFLD; NASH; Pharmacology & Pharmacy; Physical Sciences; PPARα; Science & Technology; Selective PPARα agonists; NAFLD; TG; T2D; HFD; HCC; PPARα; PPREs; NASH; RXR; Selective PPARα agonists; Hepatic steatohepatitis; DESIGN; LIPID-METABOLISM; ACID; Selective PPAR alpha agonists; LIGANDS; MECHANISM; INFLAMMATION; PPAR alpha
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2021.116193

[Display omitted] 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.