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

Abstract We have discovered and demonstrated the in vitro and in vivo PPARδ-selective activity of novel Y-shaped agonists. These compounds activated hPPARδ with EC 50 values between 1 and 523 nM. Surprisingly, compounds 10a , 11d , 11e and 11f were the most potent and most selective hPPARδ agonists with 10 4 -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.