Published in
American Chemical Society, Journal of Medicinal Chemistry, 3(59), p. 1232-1238, 2016
DOI: 10.1021/acs.jmedchem.5b01702
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Chiral Dihydrobenzofuran Acids Show Potent Retinoid X Receptor-Nuclear Receptor Related 1 Protein Dimer Activation
,
Seppe Leysen,
Marcus Malo,
Jian-Nong,
Jian-Nong Ma,
Ethan S. Burstein,
Christian Ottmann,
Luc Brunsveld ,
Roger Olsson
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- Must obtain written permission from Editor
- Must not violate ACS ethical Guidelines
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.