Oxaprozin Analogues as Selective RXR Agonists with Superior Properties and Pharmacokinetics
| Autor: | Xiaomin Ni, Apirat Chaikuad, Simone Schierle, Stefano Woltersdorf, Espen Schallmayer, Riccardo Ronchetti, Daniel Merk, Ewgenij Proschak, Beatrice Renelt, Felix F Lillich, Stefan Knapp |
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| Rok vydání: | 2021 |
| Předmět: |
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 |
| Zdroj: | Journal of medicinal chemistry. 64(8) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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