TY - JOUR
T1 - Fluorescent retinoid X receptor ligands for fluorescence polarization assay
AU - Yamada, Shoya
AU - Ohsawa, Fuminori
AU - Fujii, Shuji
AU - Shinozaki, Ryosuke
AU - Makishima, Makoto
AU - Naitou, Hirotaka
AU - Enomoto, Shuichi
AU - Tai, Akihiro
AU - Kakuta, Hiroki
N1 - Funding Information:
The authors are grateful to the SC-NMR Laboratory of Okayama University for the NMR experiments. 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 also grateful to Mr. Ryosuke Fukai, 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 receptor (RXR) agonists are candidate agents for the treatment of metabolic syndrome and type 2 diabetes via activation of peroxisome proliferator-activated receptor (PPAR)/RXR or liver X receptor (LXR)/RXR-heterodimers, which control lipid and glucose metabolism. Reporter gene assays or binding assays with radiolabeled compounds are available for RXR ligand screening, but are unsuitable for high-throughput screening. Therefore, as a first step towards stabilizing a fluorescence polarization (FP) assay system for high-throughput RXR ligand screening, we synthesized fluorescent RXR ligands by modification of the lipophilic domain of RXR ligands with a carbostyril fluorophore, and selected the fluorescent RXR agonist 6-[ethyl(1-isobutyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinolin-7-yl)amino] nicotinic acid 8d for further characterization. Compound 8d showed FP in the presence of RXR and the FP was decreased in the presence of the RXR agonist LGD1069 (2). This compound should be a lead compound for use in high-throughput assay systems for screening RXR ligands.
AB - Retinoid X receptor (RXR) agonists are candidate agents for the treatment of metabolic syndrome and type 2 diabetes via activation of peroxisome proliferator-activated receptor (PPAR)/RXR or liver X receptor (LXR)/RXR-heterodimers, which control lipid and glucose metabolism. Reporter gene assays or binding assays with radiolabeled compounds are available for RXR ligand screening, but are unsuitable for high-throughput screening. Therefore, as a first step towards stabilizing a fluorescence polarization (FP) assay system for high-throughput RXR ligand screening, we synthesized fluorescent RXR ligands by modification of the lipophilic domain of RXR ligands with a carbostyril fluorophore, and selected the fluorescent RXR agonist 6-[ethyl(1-isobutyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinolin-7-yl)amino] nicotinic acid 8d for further characterization. Compound 8d showed FP in the presence of RXR and the FP was decreased in the presence of the RXR agonist LGD1069 (2). This compound should be a lead compound for use in high-throughput assay systems for screening RXR ligands.
KW - Carbostyril
KW - Fluorescence polarization
KW - Molecular design
KW - Retinoid X receptor
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U2 - 10.1016/j.bmcl.2010.07.011
DO - 10.1016/j.bmcl.2010.07.011
M3 - Article
C2 - 20667726
AN - SCOPUS:77955661848
SN - 0960-894X
VL - 20
SP - 5143
EP - 5146
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 17
ER -
