Identification of novel multitargeted PPARa/?/d pan agonists by core hopping of rosiglitazone

Wang, Xue-Jiao; Zhang, Jun; Wang, Shu-Qing; Xu, Wei-Ren; Cheng, Xian-Chao; Wang, Run-Ling

Peroxisome proliferator-activated receptors (PPARs) are nuclear ligand-activated transcription factors and include three subtypes, namely PPARα, PPARγ, and PPARδ. [1] [2] [3] The drugs targeting PPARs mainly include: 1) PPARγ agonists 4 such as rosiglitazone and pioglitazone, which are used as antidiabetic drugs and also possess anti-inflammatory or antineoplastic activities, 5, 6 and 2) PPARα agonists such as fenofibrate and bezafibrate, which are used as antilipemic drugs ( Figure 1 ). 7, 8 Rosiglitazone and pioglitazone have shown side effects in clinical use, such as liver function abnormity, edema, and weight gain. 9 Especially in 2007, Nissen and Wolski 10 reported the cardiac safety of rosiglitazone, which showed that singly selective agonism of PPARγ not only enhanced insulin sensitivity and the therapeutic effect of insulin metabolism but also caused edema, weight gain, and the potential risk of heart failure.