2. Academic Validation
  3. Modification at the Lipophilic Domain of RXR Agonists Differentially Influences Activation of RXR Heterodimers

Modification at the Lipophilic Domain of RXR Agonists Differentially Influences Activation of RXR Heterodimers

  • ACS Med Chem Lett. 2010 Aug 27;1(9):521-5. doi: 10.1021/ml100184k.
Fuminori Ohsawa 1,  Ken-Ichi Morishita 2,  Shoya Yamada 2,  Makoto Makishima 3,  Hiroki Kakuta 2
Affiliations

Affiliations

  • 1 Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-Naka, Kita-Ku, Okayama 700-8530, Japan ; Multiple Molecular Imaging Research Laboratory, RIKEN Center for Molecular Imaging Science, Minatojima-minamimachi 6-7-3, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
  • 2 Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-Naka, Kita-Ku, Okayama 700-8530, Japan.
  • 3 Division of Biochemistry, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan.
PMID: 24900241 DOI: 10.1021/ml100184k
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.

Keywords

LXR; PPAR; RXR agonists; heterodimer activation; permissive heterodimers; reporter gene assay.

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