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 Won; Tae Gu Lee; Jihye Choi; Mi Sun Park; Chaok Seok; Jungwook Chin; Heonjoong Kang

doi:10.1016/j.ejmech.2012.03.055

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. Epub 2012 Apr 6.

Affiliation

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Obesity Agents / chemical synthesis*
Anti-Obesity Agents / chemistry
Anti-Obesity Agents / pharmacology*
Anti-Obesity Agents / therapeutic use
Chemistry Techniques, Synthetic
Diet, High-Fat / adverse effects
Dose-Response Relationship, Drug
Drug Design*
Humans
Mice
Models, Molecular
Obesity / drug therapy
Obesity / etiology
PPAR delta / agonists*
PPAR delta / chemistry
Protein Conformation

Substances

Anti-Obesity Agents
PPAR delta