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, Toshitaka Oohashi, Makoto Makishima, Hirotaka Naitou, Erika Ishitsubo, Hiroaki Tokiwa, Akihiro Tai, Hiroki Kakuta

Research output: Contribution to journalArticle

20 Citations (Scopus)

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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Carboxylic Acids
Glucose
Peroxisome Proliferator-Activated Receptors
Oral Administration
pyridine
alkoxyl radical
1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Medicine(all)

Cite this

RXR partial agonist produced by side chain repositioning of alkoxy RXR full agonist retains antitype 2 diabetes activity without the adverse effects. / Kawata, Kohei; Morishita, Ken Ichi; Nakayama, Mariko; Yamada, Shoya; Kobayashi, Toshiki; Furusawa, Yuki; Arimoto, Sakae; Oohashi, Toshitaka; Makishima, Makoto; Naitou, Hirotaka; Ishitsubo, Erika; Tokiwa, Hiroaki; Tai, Akihiro; Kakuta, Hiroki.

In: Journal of Medicinal Chemistry, Vol. 58, No. 2, 22.01.2015, p. 912-926.

Research output: Contribution to journalArticle

Kawata, K, Morishita, KI, Nakayama, M, Yamada, S, Kobayashi, T, Furusawa, Y, Arimoto, 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, vol. 58, no. 2, pp. 912-926. https://doi.org/10.1021/jm501863r
Kawata, Kohei ; Morishita, Ken Ichi ; Nakayama, Mariko ; Yamada, Shoya ; Kobayashi, Toshiki ; Furusawa, Yuki ; Arimoto, Sakae ; Oohashi, Toshitaka ; Makishima, Makoto ; Naitou, Hirotaka ; Ishitsubo, Erika ; Tokiwa, Hiroaki ; Tai, Akihiro ; Kakuta, Hiroki. / RXR partial agonist produced by side chain repositioning of alkoxy RXR full agonist retains antitype 2 diabetes activity without the adverse effects. In: Journal of Medicinal Chemistry. 2015 ; Vol. 58, No. 2. pp. 912-926.
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T1 - RXR partial agonist produced by side chain repositioning of alkoxy RXR full agonist retains antitype 2 diabetes activity without the adverse effects

AU - Kawata, Kohei

AU - Morishita, Ken Ichi

AU - Nakayama, Mariko

AU - Yamada, Shoya

AU - Kobayashi, Toshiki

AU - Furusawa, Yuki

AU - Arimoto, Sakae

AU - Oohashi, Toshitaka

AU - Makishima, Makoto

AU - Naitou, Hirotaka

AU - Ishitsubo, Erika

AU - Tokiwa, Hiroaki

AU - Tai, Akihiro

AU - Kakuta, Hiroki

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Y1 - 2015/1/22

N2 - 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.

AB - 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.

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