Reduction of lipophilicity at the lipophilic domain of RXR agonists enables production of subtype preference: RXRα-preferential agonist possessing a sulfonamide moiety

Kayo Takamatsu, Atsushi Takano, Nobumasa Yakushiji, Ken Ichi Morishita, Nobuyasu Matsuura, Makoto Makishima, Hamed Ismail Ali, Eiichi Akaho, Akihiro Tai, Kenji Sasaki, Hiroki Kakuta

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Retinoid X receptor agonists (RXR agonists, rexinoids) are interesting candidates for the treatment of cancers such as tamoxifen-resistant breast cancer and taxol-resistant lung cancer. However, well-known RXR agonists possess a strong lipophilic character. In addition, although RXR has three subtypes, no subtype-selective RXR agonists are known. Thus we aimed to produce less-lipophilic and subtype-selective RXR agonists. By designing sulfonamide-type RXR agonists, 4-[N-methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydro-2-naphthyl)amino]benzoic acid (8a) was found to prefer RXRα over RXRβ and RXRγ, although the potencyis less than the potencies of well-known RXR pan-agonists. Moreover, our results suggest that the reduction of lipophilicityat the hydrophobic interaction region of RXR agonists enables production of RXR subtype preference. Our finding will be useful for the creation of more potent and less-lipophilic subtype-selective RXR agonists aimed at the reduction of undesirable side effects.

Original languageEnglish
Pages (from-to)454-460
Number of pages7
JournalChemMedChem
Volume3
Issue number3
DOIs
Publication statusPublished - Mar 14 2008

Keywords

  • Docking simulations
  • RXR agonists
  • Subtype preference
  • Subtype selectivity
  • Sulfonamides
  • Synergistic effects

ASJC Scopus subject areas

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

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