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ACS Med Chem Lett. 2019 Jan 4;10(2):203-208. doi: 10.1021/acsmedchemlett.8b00551. eCollection 2019 Feb 14.

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

Author information

1
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
2
Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Theodor-Stern-Kai 7, D-60596 Frankfurt, Germany.

Abstract

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.

PMID:
30783504
PMCID:
PMC6378677
[Available on 2020-02-14]
DOI:
10.1021/acsmedchemlett.8b00551

Conflict of interest statement

The authors declare no competing financial interest.

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