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 language | English |
|---|---|
| Pages (from-to) | 5139-5142 |
| Number of pages | 4 |
| Journal | Bioorganic and Medicinal Chemistry Letters |
| Volume | 20 |
| Issue number | 17 |
| DOIs | |
| Publication status | Published - Sep 1 2010 |
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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 journal › Article
}
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 -