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, Organic Chemistry

University of Gothenburg

Anja Schäfer

University of Gothenburg

Marcel Scheepstra

Technische Universiteit Eindhoven

Seppe Leysen

Technische Universiteit Eindhoven

Marcus Malo

University of Gothenburg

Jian-Nong Ma

ACADIA Pharmaceuticals Inc.

Ethan S Burstein

ACADIA Pharmaceuticals Inc.

Christian Ottmann

Technische Universiteit Eindhoven

Luc Brunsveld

Technische Universiteit Eindhoven

Roger Olsson

University of Gothenburg

Journal of Medicinal Chemistry

0022-2623 (ISSN) 1520-4804 (eISSN)

Vol. 59 1232-1238

Roots

Basic sciences

Subject Categories

Organic Chemistry

DOI

10.1021/acs.jmedchem.5b01702

PubMed

26820900