Discovery and structure-activity relationship study of 2-piperazinyl-benzo- thiazole derivatives as potent and selective PPARδ agonists

Peroxisome proliferator-activated receptor d (PPARd) is considered to be a target for treating metabolic syndrome, whereas there is no PPARd agonist in clinical use. Previously, we have reported the discovery of 2-(1-piperidinyl)-1,3-benzothiazole derivatives as a new series of PPARd agonists using docking-based virtual screening techniques. In this study, we performed the further optimization study of the lead compound 1 focusing on improvement of hydrophobic interactions in the binding site to enhance agonist efficacy for PPARd and subtype selectivity, thereby discovering a novel PPARd agonist 5g which exhibited high in vitro agonist activity (hPPARd, EC50 = 4.1 nM) and sufficiently high selectivity ratio over PPARa and PPAR?. Moreover, 5g revealed a significant upregulation of high-density lipoprotein cholesterol level in vivo.

Automated summary

A novel PPARd agonist 5g with high selectivity ratio and strong agonist activity was discovered through further optimization study of compound 1. Additionally, 5g showed significant upregulation of high-density lipoprotein cholesterol level in vivo.