Computer-Assisted Discovery and Structural Optimization of a Novel Retinoid X Receptor Agonist Chemotype

As universal heterodimer partners of many nuclear receptors, the retinoid X receptors (RXRs) constitute key transcription factors. They regulate cell proliferation, differentiation, inflammation, and metabolic homeostasis and have recently been proposed as potential drug targets for neurodegenerativ...

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Bibliographic Details
Published in:ACS medicinal chemistry letters 2019-02, Vol.10 (2), p.203-208
Main Authors: Heitel, Pascal, Gellrich, Leonie, Kalinowsky, Lena, Heering, Jan, Kaiser, Astrid, Ohrndorf, Julia, Proschak, Ewgenij, Merk, Daniel
Format: Article
Language:English
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Letter
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Summary:As universal heterodimer partners of many nuclear receptors, the retinoid X receptors (RXRs) constitute key transcription factors. They regulate cell proliferation, differentiation, inflammation, and metabolic homeostasis and have recently been proposed as potential drug targets for neurodegenerative and inflammatory diseases. Owing to the hydrophobic nature of RXR ligand binding sites, available synthetic RXR ligands are lipophilic, and their structural diversity is limited. Here, we disclose the computer-assisted discovery of a novel RXR agonist chemotype and its systematic optimization toward potent RXR modulators. We have developed a nanomolar RXR agonist with high selectivity among nuclear receptors and superior physicochemical properties compared to classical rexinoids that appears suitable for in vivo applications and as lead for future RXR-targeting medicinal chemistry.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.8b00551