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

  • Eur J Med Chem. 2012 Jul:53:190-202. doi: 10.1016/j.ejmech.2012.03.055.
Jungyeob Ham  1 ,  Hoosang Hwang ,  Euno Kim ,  Jeong-Ah Kim ,  Sung Jin Cho ,  Jaeyoung Ko ,  Woojin Lee ,  Jaehwan Lee ,  Harish Holla ,  Joydeep Banerjee ,  Seokho Kim ,  Inho Yang ,  Hyun Joo Lee ,  Kyoungjin Shin ,  Hyukjae Choi ,  Sang-Jip Nam ,  Jungae Tak ,  Dongyup Hahn ,  Taekyung Oh ,  Dong Hwan Won ,  Tae Gu Lee ,  Jihye Choi ,  Mi Sun Park ,  Chaok Seok ,  Jungwook Chin ,  Heonjoong Kang
Affiliations
  • 1. Center for Marine Natural Products and Drug Discovery, School of Earth and Environmental Sciences, Seoul National University, NS-80, Seoul 151-747, Republic of Korea.
PMID: 22534184 DOI: 10.1016/j.ejmech.2012.03.055
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.