title: Modification at the acidic domain of RXR agonists has little effect on permissive RXR-heterodimer activation.
abstract: Retinoid X receptors (RXRs) function as homo- or heterodimers with other nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs), which are targets for treatment of hyperlipidemia and type 2 diabetes, or liver X receptors (LXRs), which are involved in glucose/lipid metabolism. PPAR/RXR or LXR/RXR are known as permissive RXR-heterodimers because they are activated by RXR agonists alone. Interestingly, the pattern of RXR-heterodimer activation is different depending on the RXR agonist structure, but the structure-activity relationship has not been reported. Here we show that modification or replacement of the carboxyl group in the acidic domain of RXR agonists has little or no effect on permissive RXR-heterodimer activation. Phosphonic acid (9), tetrazole (10), and hydroxamic acid (12) analogues were synthesized from the common bromo intermediate 7. Except for 9, these compounds showed RXR full-agonistic activities in the concentration range of 1-10 microM. The order of agonistic activity toward both PPARgamma/RXRalpha and LXRalpha/RXRalpha was the same as it was for RXR, that is, 11>10>12. These results should be useful for the development of RXR agonists with improved bioavailability.
authors.affiliation: Division of Pharmaceutical Sciences, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Tsushima-Naka, Okayama, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Fujii
authors.forename: Fuminori
authors.initials: F
authors.lastname: Ohsawa
authors.forename: Shoya
authors.initials: S
authors.lastname: Yamada
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Shinozaki
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Fukai
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
authors.forename: Shuichi
authors.initials: S
authors.lastname: Enomoto
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tai
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kakuta
mesh_terms: D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D008958:Models, Molecular; D047488:Retinoid X Receptors / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D047488:Retinoid X Receptors