1. Oxaprozin Analogues as Selective RXR Agonists with Superior Properties and Pharmacokinetics
- Author
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Xiaomin Ni, Apirat Chaikuad, Simone Schierle, Stefano Woltersdorf, Espen Schallmayer, Riccardo Ronchetti, Daniel Merk, Ewgenij Proschak, Beatrice Renelt, Felix F Lillich, and Stefan Knapp
- Subjects
Cell Survival ,Pharmacology ,Retinoid X receptor ,Molecular Dynamics Simulation ,Crystallography, X-Ray ,Ligands ,environment and public health ,01 natural sciences ,03 medical and health sciences ,Mice ,Structure-Activity Relationship ,In vivo ,Microsomes ,Oxaprozin ,Drug Discovery ,medicine ,Structure–activity relationship ,Animals ,Humans ,Protein Isoforms ,Binding site ,Receptor ,Transcription factor ,030304 developmental biology ,0303 health sciences ,Binding Sites ,Chemistry ,0104 chemical sciences ,Rats ,body regions ,010404 medicinal & biomolecular chemistry ,Retinoid X Receptors ,Nuclear receptor ,embryonic structures ,Molecular Medicine ,Pyrazoles ,lipids (amino acids, peptides, and proteins) ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug ,Half-Life - Abstract
The retinoid X receptors (RXR) are ligand-activated transcription factors involved in multiple regulatory networks as universal heterodimer partners for nuclear receptors. Despite their high therapeutic potential in many pathologies, targeting of RXR has only been exploited in cancer treatment as the currently available RXR agonists suffer from exceptional lipophilicity, poor pharmacokinetics (PK), and adverse effects. Aiming to overcome the limitations and to provide improved RXR ligands, we developed a new potent RXR ligand chemotype based on the nonsteroidal anti-inflammatory drug oxaprozin. Systematic structure-activity relationship analysis enabled structural optimization toward low nanomolar potency similar to the well-established rexinoids. Cocrystal structures of the most active derivatives demonstrated orthosteric binding, and in vivo profiling revealed superior PK properties compared to current RXR agonists. The optimized compounds were highly selective for RXR activation and induced RXR-regulated gene expression in native cellular and in vivo settings suggesting them as excellent chemical tools to further explore the therapeutic potential of RXR.
- Published
- 2021