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
N1 - Funding Information:
The authors are grateful to the staff of the SC-NMR Laboratory of Okayama University for performing the NMR experiments. The authors are also grateful to Professor Miyachi for presenting TIPP-703 and carba-T0901317. This work was partially supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Culture and Sports of Japan . The authors are grateful to Ms. Mariko Nakayama and Mr. Kohei Kawata for helpful discussions during the preparation of this manuscript.
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 - PPAR
KW - Permissive heterodimers
KW - RXR agonists
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U2 - 10.1016/j.bmcl.2010.07.012
DO - 10.1016/j.bmcl.2010.07.012
M3 - Article
C2 - 20656484
AN - SCOPUS:77955654529
VL - 20
SP - 5139
EP - 5142
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 17
ER -
