Modification at the acidic domain of RXR agonists has little effect on permissive RXR-heterodimer activation

Shuji Fujii, Fuminori Ohsawa, Shoya Yamada, Ryosuke Shinozaki, Ryosuke Fukai, Makoto Makishima, Shuichi Enomoto, Akihiro Tai, Hiroki Kakuta

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Retinoid X receptors (RXRs) function as homo- or heterodimers with other nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs), which are targets for treatment of hyperlipidemia and type 2 diabetes, or liver X receptors (LXRs), which are involved in glucose/lipid metabolism. PPAR/RXR or LXR/RXR are known as permissive RXR-heterodimers because they are activated by RXR agonists alone. Interestingly, the pattern of RXR-heterodimer activation is different depending on the RXR agonist structure, but the structure-activity relationship has not been reported. Here we show that modification or replacement of the carboxyl group in the acidic domain of RXR agonists has little or no effect on permissive RXR-heterodimer activation. Phosphonic acid (9), tetrazole (10), and hydroxamic acid (12) analogues were synthesized from the common bromo intermediate 7. Except for 9, these compounds showed RXR full-agonistic activities in the concentration range of 1-10 μM. The order of agonistic activity toward both PPARγ/RXRα and LXRα/RXRα was the same as it was for RXR, that is, 11 > 10 > 12. These results should be useful for the development of RXR agonists with improved bioavailability.

Original languageEnglish
Pages (from-to)5139-5142
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume20
Issue number17
DOIs
Publication statusPublished - Sep 1 2010

Fingerprint

Retinoid X Receptors
Chemical activation
Peroxisome Proliferator-Activated Receptors
Liver
Hydroxamic Acids
Structure-Activity Relationship
Cytoplasmic and Nuclear Receptors
Medical problems
Hyperlipidemias
Lipid Metabolism

Keywords

  • Carboxylic analogues
  • Docking simulation
  • LXR
  • Permissive heterodimers
  • PPAR
  • RXR agonists

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Modification at the acidic domain of RXR agonists has little effect on permissive RXR-heterodimer activation. / Fujii, Shuji; Ohsawa, Fuminori; Yamada, Shoya; Shinozaki, Ryosuke; Fukai, Ryosuke; Makishima, Makoto; Enomoto, Shuichi; Tai, Akihiro; Kakuta, Hiroki.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 20, No. 17, 01.09.2010, p. 5139-5142.

Research output: Contribution to journalArticle

Fujii, Shuji ; Ohsawa, Fuminori ; Yamada, Shoya ; Shinozaki, Ryosuke ; Fukai, Ryosuke ; Makishima, Makoto ; Enomoto, Shuichi ; Tai, Akihiro ; Kakuta, Hiroki. / Modification at the acidic domain of RXR agonists has little effect on permissive RXR-heterodimer activation. In: Bioorganic and Medicinal Chemistry Letters. 2010 ; Vol. 20, No. 17. pp. 5139-5142.
@article{bdbbbefe32d9499e96b1c2e5c3c76397,
title = "Modification at the acidic domain of RXR agonists has little effect on permissive RXR-heterodimer activation",
abstract = "Retinoid X receptors (RXRs) function as homo- or heterodimers with other nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs), which are targets for treatment of hyperlipidemia and type 2 diabetes, or liver X receptors (LXRs), which are involved in glucose/lipid metabolism. PPAR/RXR or LXR/RXR are known as permissive RXR-heterodimers because they are activated by RXR agonists alone. Interestingly, the pattern of RXR-heterodimer activation is different depending on the RXR agonist structure, but the structure-activity relationship has not been reported. Here we show that modification or replacement of the carboxyl group in the acidic domain of RXR agonists has little or no effect on permissive RXR-heterodimer activation. Phosphonic acid (9), tetrazole (10), and hydroxamic acid (12) analogues were synthesized from the common bromo intermediate 7. Except for 9, these compounds showed RXR full-agonistic activities in the concentration range of 1-10 μM. The order of agonistic activity toward both PPARγ/RXRα and LXRα/RXRα was the same as it was for RXR, that is, 11 > 10 > 12. These results should be useful for the development of RXR agonists with improved bioavailability.",
keywords = "Carboxylic analogues, Docking simulation, LXR, Permissive heterodimers, PPAR, RXR agonists",
author = "Shuji Fujii and Fuminori Ohsawa and Shoya Yamada and Ryosuke Shinozaki and Ryosuke Fukai and Makoto Makishima and Shuichi Enomoto and Akihiro Tai and Hiroki Kakuta",
year = "2010",
month = "9",
day = "1",
doi = "10.1016/j.bmcl.2010.07.012",
language = "English",
volume = "20",
pages = "5139--5142",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "17",

}

TY - JOUR

T1 - Modification at the acidic domain of RXR agonists has little effect on permissive RXR-heterodimer activation

AU - Fujii, Shuji

AU - Ohsawa, Fuminori

AU - Yamada, Shoya

AU - Shinozaki, Ryosuke

AU - Fukai, Ryosuke

AU - Makishima, Makoto

AU - Enomoto, Shuichi

AU - Tai, Akihiro

AU - Kakuta, Hiroki

PY - 2010/9/1

Y1 - 2010/9/1

N2 - Retinoid X receptors (RXRs) function as homo- or heterodimers with other nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs), which are targets for treatment of hyperlipidemia and type 2 diabetes, or liver X receptors (LXRs), which are involved in glucose/lipid metabolism. PPAR/RXR or LXR/RXR are known as permissive RXR-heterodimers because they are activated by RXR agonists alone. Interestingly, the pattern of RXR-heterodimer activation is different depending on the RXR agonist structure, but the structure-activity relationship has not been reported. Here we show that modification or replacement of the carboxyl group in the acidic domain of RXR agonists has little or no effect on permissive RXR-heterodimer activation. Phosphonic acid (9), tetrazole (10), and hydroxamic acid (12) analogues were synthesized from the common bromo intermediate 7. Except for 9, these compounds showed RXR full-agonistic activities in the concentration range of 1-10 μM. The order of agonistic activity toward both PPARγ/RXRα and LXRα/RXRα was the same as it was for RXR, that is, 11 > 10 > 12. These results should be useful for the development of RXR agonists with improved bioavailability.

AB - Retinoid X receptors (RXRs) function as homo- or heterodimers with other nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs), which are targets for treatment of hyperlipidemia and type 2 diabetes, or liver X receptors (LXRs), which are involved in glucose/lipid metabolism. PPAR/RXR or LXR/RXR are known as permissive RXR-heterodimers because they are activated by RXR agonists alone. Interestingly, the pattern of RXR-heterodimer activation is different depending on the RXR agonist structure, but the structure-activity relationship has not been reported. Here we show that modification or replacement of the carboxyl group in the acidic domain of RXR agonists has little or no effect on permissive RXR-heterodimer activation. Phosphonic acid (9), tetrazole (10), and hydroxamic acid (12) analogues were synthesized from the common bromo intermediate 7. Except for 9, these compounds showed RXR full-agonistic activities in the concentration range of 1-10 μM. The order of agonistic activity toward both PPARγ/RXRα and LXRα/RXRα was the same as it was for RXR, that is, 11 > 10 > 12. These results should be useful for the development of RXR agonists with improved bioavailability.

KW - Carboxylic analogues

KW - Docking simulation

KW - LXR

KW - Permissive heterodimers

KW - PPAR

KW - RXR agonists

UR - http://www.scopus.com/inward/record.url?scp=77955654529&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77955654529&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2010.07.012

DO - 10.1016/j.bmcl.2010.07.012

M3 - Article

VL - 20

SP - 5139

EP - 5142

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 17

ER -