Chiral Dihydrobenzofuran Acids Show Potent Retinoid X Receptor–Nuclear Receptor Related 1 Protein Dimer Activation
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- 作者：Henrik Sundén ; Anja Sch?fer ; Marcel Scheepstra ; Seppe Leysen ; Marcus Malo ; Jian-Nong Ma ; Ethan S. Burstein ; Christian Ottmann ; Luc Brunsveld ; Roger Olsson
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：February 11, 2016
- 年：2016
- 卷：59
- 期：3
- 页码：1232-1238
- 全文大小：431K
- ISSN：1520-4804
文摘
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 (pECub>50 ub> of 8.2) and RXR–Nurr1. The X-ray structure shows enantiomeric discrimination where 9a optimally addresses the ligand binding pocket of RXR.