Chiral Dihydrobenzofuran Acids Show Potent Retinoid X Receptor-Nuclear Receptor Related 1 Protein Dimer Activation

Journal of Medicinal Chemistry
Henrik SundénRoger Olsson

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.

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Citations

Jul 12, 2017·ACS Chemical Neuroscience·Marcel ScheepstraLuc Brunsveld
Apr 4, 2019·Medicinal Research Reviews·Nathalia Rodrigues de Almeida, Martin Conda-Sheridan
Apr 27, 2019·Molecular and Cellular Endocrinology·Wojciech KrężelAngel R de Lera
Jul 13, 2021·Journal of Medicinal Chemistry·Sabine WillemsDaniel Merk

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