Modification at the lipophilic domain of RXR agonists differentially influences activation of RXR heterodimers

Fuminori Ohsawa, Ken Ichi Morishita, Shoya Yamada, Makoto Makishima, Hiroki Kakuta

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

RXR permissive heterodimers are reported to be activated differently depending upon the chemical structure of RXR agonists, but the relationship of agonist structure to differential heterodimer activation has not been explored in detail. In this study, we performed systematic conversion of the alkoxy side chain of 5a (6-[ethyl-(3-isopropoxy-4-isopropylphenyl)amino]nicotinic acid, NEt-3IP) and evaluated the RXR-, PPAR/RXR-, and LXR/RXR-agonist activities of the products. The cyclopropylmethoxy analogue (5c) showed similar RXR- and LXR/RXR-agonistic activities to the benzyloxy analogue (5i) and n-propoxy analogue (5k) but exhibited more potent PPAR/RXR-agonistic activity than 5i or 5k. Differential modulation of RXR heterodimer-activating ability by conversion of the alkoxy group located in the lipophilic domain of the RXR-agonist common structure is expected be a useful approach in the design of new RXR agonists for the treatment of hyperlipidemia or type 2 diabetes.

Original languageEnglish
Pages (from-to)521-525
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume1
Issue number9
DOIs
Publication statusPublished - Dec 9 2010

Keywords

  • LXR
  • PPAR
  • RXR agonists
  • heterodimer activation
  • permissive heterodimers
  • reporter gene assay

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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