RXR partial agonist produced by side chain repositioning of alkoxy RXR full agonist retains antitype 2 diabetes activity without the adverse effects

Kohei Kawata, Ken Ichi Morishita, Mariko Nakayama, Shoya Yamada, Toshiki Kobayashi, Yuki Furusawa, Sakae Arimoto-Kobayashi, Toshitaka Oohashi, Makoto Makishima, Hirotaka Naitou, Erika Ishitsubo, Hiroaki Tokiwa, Akihiro Tai, Hiroki Kakuta

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Abstract

We previously reported RXR partial agonist CBt-PMN (1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid: 5, EC50 = 143 nM, Emax = 75%), which showed a potent glucose-lowering effect without causing serious adverse effects. However, it remains important to elucidate the structural requirements for RXR efficacy and the glucose-lowering effect because RXR-permissive heterodimers such as PPAR/RXR or LXR/RXR are reported to be activated differently depending upon the chemical structure of RXR agonists. In this work, we show that an RXR partial agonist, NEt-4IB (6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: 8b, EC50 = 169 nM, Emax = 55%), can be obtained simply by repositioning the side chains (interchanging the isobutoxy and isopropoxy groups) at the hydrophobic moiety of the RXR full agonist NEt-3IB (6-[ethyl-(3-isobutoxy-4-isopropylphenyl)amino]pyridine-3-carboxylic acid: 7b, EC50 = 19 nM). NEt-4IB (8b) showed antitype 2 diabetes activity without the above side effects upon repeated oral administration to mice at 10 mg/kg/day, similarly to 5.

Original languageEnglish
Pages (from-to)912-926
Number of pages15
JournalJournal of medicinal chemistry
Volume58
Issue number2
DOIs
Publication statusPublished - Jan 22 2015

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Kawata, K., Morishita, K. I., Nakayama, M., Yamada, S., Kobayashi, T., Furusawa, Y., Arimoto-Kobayashi, S., Oohashi, T., Makishima, M., Naitou, H., Ishitsubo, E., Tokiwa, H., Tai, A., & Kakuta, H. (2015). RXR partial agonist produced by side chain repositioning of alkoxy RXR full agonist retains antitype 2 diabetes activity without the adverse effects. Journal of medicinal chemistry, 58(2), 912-926. https://doi.org/10.1021/jm501863r