Discovery, design and synthesis of Y-shaped peroxisome proliferator-activated receptor δ agonists as potent anti-obesity agents in vivo

We have discovered and demonstrated the in vitro and in vivo PPARδ-selective activity of novel Y-shaped agonists. These compounds activated hPPARδ with EC50 values between 1 and 523 nM. Surprisingly, compounds 10a, 11d, 11e and 11f were the most potent and most selective hPPARδ agonists with 104-fold selectivity over the other two subtypes, namely, hPPARα and hPPARγ. The PPARδ ligands 10a, 11e and 11f showed good bioavailability and in vivo efficacy.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► We synthesized a series of Y-shaped analogs with alkyl and arylalkyl substituents. ► Compounds 10a, 11d, 11e and 11f displayed excellent selectivity and potency. ► Selective PPARδ agonists showed good bioavailability and in vivo efficacy.