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 PPAR delta-selective activity of novel Y-shaped agonists. These compounds activated hPPAR delta with EC50 values between 1 and 523 nM. Surprisingly, compounds 10a, 11d, 11e and 11f were the most potent and most selective hPPAR delta agonists with 10(4)-fold selectivity over the other two subtypes, namely, hPPAR alpha and hPPAR gamma. The PPAR delta ligands 10a, 11e and 11f showed good bioavailability and in vivo efficacy. (C) 2012 Elsevier Masson SAS. All rights reserved.