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.
Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
Bioorg Med Chem. 2021 Jul 1;41:116193. doi: 10.1016/j.bmc.2021.116193. Epub 2021 May 1.
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.
非酒精性脂肪性肝病 (NAFLD) 是一种严重的肝脏疾病，可导致严重的肝脏并发症，包括非酒精性脂肪性肝炎 (NASH)。核受体过氧化物酶体增殖物激活受体α (PPARα) 因其在调节脂质代谢、促进甘油三酯氧化和抑制肝脏炎症方面的独特功能，作为治疗 2 型糖尿病和相关疾病的潜在药物靶点，引起了特别关注，因此人们对 PPARα 激动剂作为治疗非酒精性脂肪性肝病的潜在疗法产生了兴趣。然而，PPARα 如何协调各种代谢途径中潜在的非酒精性脂肪性肝病和 NASH 的治疗仍然不清楚。在这里，我们表明新型选择性 PPARα 调节剂 DY 系列通过上调直接参与非酒精性脂肪性肝病和 NASH 的 PPARα 靶基因来激活 PPARα。描述了新型 DY 系列 PPARα 激动剂的设计、合成、对接研究以及体外和体内评价。
