title: Modification at the Lipophilic Domain of RXR Agonists Differentially Influences Activation of RXR Heterodimers.
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.
authors.affiliation: 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.
authors.forename: Fuminori
authors.initials: F
authors.lastname: Ohsawa
authors.affiliation: 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.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Morishita
authors.affiliation: 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.
authors.forename: Shoya
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Division of Biochemistry, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
authors.affiliation: 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.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kakuta
keywords: LXR; PPAR; RXR agonists; heterodimer activation; permissive heterodimers; reporter gene assay