Discovery of a potent retinoid X receptor antagonist structurally closely related to RXR agonist NEt-3IB

Mariko Nakayama, Shoya Yamada, Fuminori Ohsawa, Yui Ohta, Kohei Kawata, Makoto Makishima, Hiroki Kakuta

Research output: Contribution to journalArticle

11 Citations (Scopus)


We discovered a potent retinoid X receptor (RXR) antagonist, 6-[N-ethyl-N-(5-isobutoxy-4-isopropyl-2-(E)-styrylphenyl)amino]nicotinic acid (13e), that is structurally closely related to the RXR full agonist 6-[N-ethyl-N-(3-isobutoxy-4-isopropylphenyl)amino]nicotinic acid (NEt-3IB) (4). Compound 13e was synthesized via a simple route from 11, a methyl ester precursor of 4. Because 11 possesses high electrophilic reactivity because of the amino and alkoxy groups, it was readily transformed to 12 by iodization, and the iodine atom of 12 was converted to a C-C or C-N bond by means of palladium-catalyzed reaction to afford 13. Transcriptional activation assay revealed that 13g (in which the iodine atom was replaced with an amino group) is a weak RXR agonist, while 13d (a phenyl group), 13e (a styryl group), and 13f (an anilino group) are RXR antagonists. Among them, 13e was found to be more potent than the known RXR antagonist PA452 (9).

Original languageEnglish
Pages (from-to)896-900
Number of pages5
JournalACS Medicinal Chemistry Letters
Issue number12
Publication statusPublished - Dec 8 2011



  • agonists
  • antagonists
  • nuclear receptors
  • retinoids
  • RXR
  • Synthetic route

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

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