The first potent subtype-selective retinoid X receptor (RXR) agonist possessing a 3-isopropoxy-4-isopropylphenylamino moiety, NEt-3IP (RXRα/β-dual agonist)

Kayo Takamatsu, Atsushi Takano, Nobumasa Yakushiji, Kazunori Morohashi, Kenichi Morishita, Nobuyasu Matsuura, Makoto Makishima, Akihiro Tai, Kenji Sasaki, Hiroki Kakuta

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Retinoid X receptor (RXR) agonists (rexinoids) are attracting much attention for their use in treatment of cancers, including tamoxifen-resistant breast cancer and taxol-resistant lung cancer, and metabolic disease. However, known RXR agonists have a highly lipophilic character. In addition, no subtype-selective RXR agonists have been found. We previously reported an RXRα-preferential agonist 4-[N-methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydro-2-naphthyl)amino]benzoic acid (6a). The RXR agonistic activity is much less than that of well-known RXR agonists. To develop potent, less-lipophilic, and subtype-selective RXR agonists, we created new RXR agonists possessing alkoxy and isopropyl groups as a lipophilic domain of the common structure of well-known RXR agonists. As a result, compounds possessing branchedalkoxy groups, 6-[N-ethyl-N-(3-isopropoxy-4-isopropylphenyl) amino]nicotinic acid(NEt-3 IP: 7a) and6-[ N-ethyl-N-(3-isobutoxy-4- isopropylphenyl)amino]nicotinic acid (NEt-3IB : 7c), showed RXR agonistic activity as potent as, or more potent than, the activities of representative RXR agonists. Moreover, NEt-3IP (7a) was found to be the first RXRα/β- selective (or RXRα/β-dual) agonist. Being potent, less lipophilic, and having RXR subtype-selective activity, NEt-3IP (7a) is expected to become a new drug candidate and to be a useful biological tool for clarifying each RXR subtype function.

Original languageEnglish
Pages (from-to)780-787
Number of pages8
JournalChemMedChem
Volume3
Issue number5
DOIs
Publication statusPublished - May 19 2008

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Retinoid X Receptors
Niacin
Benzoic Acid
Metabolic Diseases
Tamoxifen
Paclitaxel

Keywords

  • Cell differentiation
  • Dual agonist
  • RXR agonists
  • Subtype selective
  • Synergistic effect

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

Cite this

The first potent subtype-selective retinoid X receptor (RXR) agonist possessing a 3-isopropoxy-4-isopropylphenylamino moiety, NEt-3IP (RXRα/β-dual agonist). / Takamatsu, Kayo; Takano, Atsushi; Yakushiji, Nobumasa; Morohashi, Kazunori; Morishita, Kenichi; Matsuura, Nobuyasu; Makishima, Makoto; Tai, Akihiro; Sasaki, Kenji; Kakuta, Hiroki.

In: ChemMedChem, Vol. 3, No. 5, 19.05.2008, p. 780-787.

Research output: Contribution to journalArticle

Takamatsu, Kayo ; Takano, Atsushi ; Yakushiji, Nobumasa ; Morohashi, Kazunori ; Morishita, Kenichi ; Matsuura, Nobuyasu ; Makishima, Makoto ; Tai, Akihiro ; Sasaki, Kenji ; Kakuta, Hiroki. / The first potent subtype-selective retinoid X receptor (RXR) agonist possessing a 3-isopropoxy-4-isopropylphenylamino moiety, NEt-3IP (RXRα/β-dual agonist). In: ChemMedChem. 2008 ; Vol. 3, No. 5. pp. 780-787.
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AU - Takano, Atsushi

AU - Yakushiji, Nobumasa

AU - Morohashi, Kazunori

AU - Morishita, Kenichi

AU - Matsuura, Nobuyasu

AU - Makishima, Makoto

AU - Tai, Akihiro

AU - Sasaki, Kenji

AU - Kakuta, Hiroki

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