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

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

Department of Chemistry & Nanoscience

Research output: Contribution to journal › Article › peer-review

10 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 language	English
Pages (from-to)	190-202
Number of pages	13
Journal	European Journal of Medicinal Chemistry
Volume	53
DOIs	https://doi.org/10.1016/j.ejmech.2012.03.055
State	Published - 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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10.1016/j.ejmech.2012.03.055

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Ham, J., Hwang, H., Kim, E., Kim, J. A., Cho, S. J., Ko, J., Lee, W., Lee, J., Holla, H., Banerjee, J., Kim, S., Yang, I., Lee, H. J., Shin, K., Choi, H., Nam, S. J., Tak, J., Hahn, D., Oh, T., ... Kang, H. (2012). Discovery, design and synthesis of Y-shaped peroxisome proliferator- activated receptor δ agonists as potent anti-obesity agents in vivo. European Journal of Medicinal Chemistry, 53, 190-202. https://doi.org/10.1016/j.ejmech.2012.03.055

@article{75748ee6e296471c88074ebee99dcb07,

title = "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 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.",

keywords = "Anti-obesity, GW501516, Marine natural products, Nuclear receptors, PPARδ",

author = "Jungyeob Ham and Hoosang Hwang and Euno Kim and Kim, {Jeong Ah} and Cho, {Sung Jin} and Jaeyoung Ko and Woojin Lee and Jaehwan Lee and Harish Holla and Joydeep Banerjee and Seokho Kim and Inho Yang and Lee, {Hyun Joo} and Kyoungjin Shin and Hyukjae Choi and Nam, {Sang Jip} and Jungae Tak and Dongyup Hahn and Taekyung Oh and Won, {Dong Hwan} and Lee, {Tae Gu} and Jihye Choi and Park, {Mi Sun} and Chaok Seok and Jungwook Chin and Heonjoong Kang",

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. ",

year = "2012",

month = jul,

doi = "10.1016/j.ejmech.2012.03.055",

language = "English",

volume = "53",

pages = "190--202",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

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Ham, J, Hwang, H, Kim, E, Kim, JA, Cho, SJ, Ko, J, Lee, W, Lee, J, Holla, H, Banerjee, J, Kim, S, Yang, I, Lee, HJ, Shin, K, Choi, H, Nam, SJ, Tak, J, Hahn, D, Oh, T, Won, DH, Lee, TG, Choi, J, Park, MS, Seok, C, Chin, J & Kang, H 2012, 'Discovery, design and synthesis of Y-shaped peroxisome proliferator- activated receptor δ agonists as potent anti-obesity agents in vivo', European Journal of Medicinal Chemistry, vol. 53, pp. 190-202. https://doi.org/10.1016/j.ejmech.2012.03.055

TY - JOUR

T1 - Discovery, design and synthesis of Y-shaped peroxisome proliferator- activated receptor δ agonists as potent anti-obesity agents in vivo

AU - Ham, Jungyeob

AU - Hwang, Hoosang

AU - Kim, Euno

AU - Kim, Jeong Ah

AU - Cho, Sung Jin

AU - Ko, Jaeyoung

AU - Lee, Woojin

AU - Lee, Jaehwan

AU - Holla, Harish

AU - Banerjee, Joydeep

AU - Kim, Seokho

AU - Yang, Inho

AU - Lee, Hyun Joo

AU - Shin, Kyoungjin

AU - Choi, Hyukjae

AU - Nam, Sang Jip

AU - Tak, Jungae

AU - Hahn, Dongyup

AU - Oh, Taekyung

AU - Won, Dong Hwan

AU - Lee, Tae Gu

AU - Choi, Jihye

AU - Park, Mi Sun

AU - Seok, Chaok

AU - Chin, Jungwook

AU - Kang, Heonjoong

N1 - 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.

PY - 2012/7

Y1 - 2012/7

N2 - 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.

AB - 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.

KW - Anti-obesity

KW - GW501516

KW - Marine natural products

KW - Nuclear receptors

KW - PPARδ

UR - http://www.scopus.com/inward/record.url?scp=84861584756&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2012.03.055

DO - 10.1016/j.ejmech.2012.03.055

M3 - Article

C2 - 22534184

AN - SCOPUS:84861584756

SN - 0223-5234

VL - 53

SP - 190

EP - 202

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

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

Abstract

Bibliographical note

Keywords

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