Discovery and structure-based design of a new series of potent and selective PPARδ agonists utilizing a virtual screening method

Design, Synthesis, and Anti-Inflammatory Evaluation of a Novel PPARδ Agonist with a 4-(1-Pyrrolidinyl)piperidine Structure

“…On the other hand, cyclohexyl analogue 9 almost entirely suppressed binding activities to PPARα/γ in both species. We previously reported that a chlorine or methyl group at the 3- or 4-position was acceptable for the benzene ring substituent in the right part of the molecules to fit the narrow hydrophobic pocket . For this reason, the 4-Cl analogue of 9 was also synthesized and evaluated, showing that the 3-position substitution was indeed appropriate for the binding affinity as 10 showed lower PPARδ activity than 9 .…”

“…* p < 0.05, ** p < 0.01, *** p < 0.001 compared to the vehicle-treated group (Dunnett’s multiple comparison test). Data for hApoB100/hCETP-dTg mice were taken from a previous study …”

“…Recently we have reported the discovery of piperidinyl/ piperazinyl benzothiazole derivatives as a new series of PPARδ agonists, including compound 1, by utilizing docking-based virtual screening methods (Figure 1). 29,30 These compounds showed high agonist activity for PPARδ and subtype selectivity and also led to significant elevation of the HDL-C level in a mouse model. Here, we describe our further optimization study of lead compound 1 to develop a more promising PPARδ agonist 21 with good ADME (absorption, distribution, metabolism, and excretion) profiles.…”

“…Values are presented as mean ± SE of 14−15 or 12 mice. Data from hApoB100/hCETP-dTg mice were taken from a previous study 29.…”