title: Chiral Dihydrobenzofuran Acids Show Potent Retinoid X Receptor-Nuclear Receptor Related 1 Protein Dimer Activation.
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.
authors.affiliation: Department of Chemistry and Molecular Biology, Medicinal Chemistry, University of Gothenburg , SE-41296 Gothenburg, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Sundén
authors.affiliation: Department of Chemistry and Molecular Biology, Medicinal Chemistry, University of Gothenburg , SE-41296 Gothenburg, Sweden.|Department of Biomedical Engineering and Institute of Complex Molecular Systems, Laboratory of Chemical Biology, Technische Universiteit Eindhoven , Den Dolech 2, 5612 AZ Eindhoven, The Netherlands.
authors.forename: Anja
authors.initials: A
authors.lastname: Schäfer
authors.affiliation: Department of Biomedical Engineering and Institute of Complex Molecular Systems, Laboratory of Chemical Biology, Technische Universiteit Eindhoven , Den Dolech 2, 5612 AZ Eindhoven, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Scheepstra
authors.affiliation: Department of Biomedical Engineering and Institute of Complex Molecular Systems, Laboratory of Chemical Biology, Technische Universiteit Eindhoven , Den Dolech 2, 5612 AZ Eindhoven, The Netherlands.
authors.forename: Seppe
authors.initials: S
authors.lastname: Leysen
authors.affiliation: Department of Chemistry and Molecular Biology, Medicinal Chemistry, University of Gothenburg , SE-41296 Gothenburg, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Malo
authors.affiliation: ACADIA Pharmaceuticals Inc. , San Diego, California 92130, United States.
authors.forename: Jian-Nong
authors.initials: JN
authors.lastname: Ma
authors.affiliation: ACADIA Pharmaceuticals Inc. , San Diego, California 92130, United States.
authors.forename: Ethan S
authors.initials: ES
authors.lastname: Burstein
authors.affiliation: Department of Biomedical Engineering and Institute of Complex Molecular Systems, Laboratory of Chemical Biology, Technische Universiteit Eindhoven , Den Dolech 2, 5612 AZ Eindhoven, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Ottmann
authors.affiliation: Department of Biomedical Engineering and Institute of Complex Molecular Systems, Laboratory of Chemical Biology, Technische Universiteit Eindhoven , Den Dolech 2, 5612 AZ Eindhoven, The Netherlands.
authors.forename: Luc
authors.initials: L
authors.lastname: Brunsveld
authors.affiliation: Department of Chemistry and Molecular Biology, Medicinal Chemistry, University of Gothenburg , SE-41296 Gothenburg, Sweden.|ACADIA Pharmaceuticals Inc. , San Diego, California 92130, United States.|Chemical Biology & Therapeutics, Department of Experimental Medical Science, Lund University , Sölvegatan 19, BMC DIO, SE-221 84 Lund, Sweden.
authors.forename: Roger
authors.initials: R
authors.lastname: Olsson
mesh_terms: D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000819:agonists / Q000378:metabolism*; D055503:Protein Multimerization / Q000187:drug effects*; D047488:Retinoid X Receptors / Q000819:agonists / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D001572:Benzofurans; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D047488:Retinoid X Receptors