Chiral Dihydrobenzofuran Acids Show Potent Retinoid X Receptor-Nuclear Receptor Related 1 Protein Dimer Activation.
Journal article, 2016
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.
Author
Henrik Sundén
Chalmers, Chemistry and Chemical Engineering, Chemistry and Biochemistry
University of Gothenburg
Anja Schäfer
University of Gothenburg
Marcel Scheepstra
Eindhoven University of Technology
Seppe Leysen
Eindhoven University of Technology
Marcus Malo
University of Gothenburg
Jian-Nong Ma
ACADIA Pharmaceuticals Inc.
Ethan S Burstein
ACADIA Pharmaceuticals Inc.
Christian Ottmann
Eindhoven University of Technology
Luc Brunsveld
Eindhoven University of Technology
Roger Olsson
University of Gothenburg
Journal of Medicinal Chemistry
0022-2623 (ISSN) 1520-4804 (eISSN)
Vol. 59 3 1232-1238Roots
Basic sciences
Subject Categories
Organic Chemistry
DOI
10.1021/acs.jmedchem.5b01702
PubMed
26820900