Modification at the acidic domain of RXR agonists has little effect on permissive RXR-heterodimer activation

Bioorganic & Medicinal Chemistry Letters
Shuji FujiiHiroki Kakuta

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.

Citations

Mar 12, 2013·Journal of Medicinal Chemistry·Martin Conda-SheridanMark Cushman
Jun 2, 2011·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Hiroki Kakuta
Sep 8, 2012·Expert Opinion on Drug Discovery·Belén Vaz, Ángel R de Lera
Jan 26, 2011·Journal of Molecular Biology·Haitao ZhangXu Shen
May 11, 2011·Biochimica Et Biophysica Acta·Robert W Curley
Apr 4, 2019·Medicinal Research Reviews·Nathalia Rodrigues de Almeida, Martin Conda-Sheridan
Nov 9, 2018·Scientific Reports·Francesca GrisoniGisbert Schneider
Aug 15, 2018·International Journal of Molecular Sciences·Masaki Watanabe, Hiroki Kakuta
Dec 9, 2010·ACS Medicinal Chemistry Letters·Fuminori OhsawaHiroki Kakuta
Dec 8, 2011·ACS Medicinal Chemistry Letters·Mariko NakayamaHiroki Kakuta
Jul 30, 2010·Bioorganic & Medicinal Chemistry Letters·Shoya YamadaHiroki Kakuta

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