1. Chiral Dihydrobenzofuran Acids Show Potent Retinoid X Receptor–Nuclear Receptor Related 1 Protein Dimer Activation
- Author
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Christian Ottmann, Anja Schäfer, Ethan S. Burstein, Marcus Malo, Luc Brunsveld, Henrik Sundén, Jian-Nong Ma, Seppe Leysen, Roger Olsson, Marcel Scheepstra, and Chemical Biology
- Subjects
Models, Molecular ,0301 basic medicine ,Agonist ,Stereochemistry ,medicine.drug_class ,Dimer ,Nuclear receptor related-1 protein ,Retinoid X receptor ,Crystallography, X-Ray ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Drug Discovery ,medicine ,Humans ,Structure–activity relationship ,Benzofurans ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Chemistry ,organic chemicals ,Enantioselective synthesis ,3. Good health ,body regions ,Retinoid X Receptors ,030104 developmental biology ,Nuclear receptor ,Biochemistry ,embryonic structures ,biology.protein ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Protein Multimerization ,Enantiomer ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery - Abstract
The nuclear receptor Nurr1 can be activated by RXR via heterodimerization (RXR-Nurr1) and is a promising target for treating neurodegenerative diseases. We herein report the enantioselective synthesis and SAR of sterically constricted benzofurans at RXR. The established SAR, using whole cell functional assays, lead to the full agonist 9a at RXR (pEC50 of 8.2) and RXR-Nurr1. The X-ray structure shows enantiomeric discrimination where 9a optimally addresses the ligand binding pocket of RXR.
- Published
- 2016