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

Jungyeob Ham, 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 WonTae Gu Lee, Jihye Choi, Mi Sun Park, Chaok Seok, Jungwook Chin, Heonjoong Kang

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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 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.

Original languageEnglish
Pages (from-to)190-202
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume53
DOIs
StatePublished - Jul 2012

Bibliographical note

Funding Information:
We are grateful to members of our laboratory. This work was supported by the Marine Biotechnology Program, Ministry of Land, Transport and Maritime Affairs . H. H., J.H., E. K., J. K., I. Y. and J. C. were in part supported by the BK21 program, Ministry of Education, Science and Technology, Korea.

Keywords

  • Anti-obesity
  • GW501516
  • Marine natural products
  • Nuclear receptors
  • PPARδ

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