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

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 SAP, of sterically constricted benzofurans at RXR The established SAR, using whole cell functi...

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Veröffentlicht in:Journal of medicinal chemistry Jg. 59; H. 3; S. 1232 - 1238
Hauptverfasser: Sunden, Henrik, Schafer, Anja, Scheepstra, Marcel, Leysen, Seppe, Malo, Marcus, Ma, Jian-Nong, Burstein, Ethan S., Ottmann, Christian, Brunsveld, Luc, Olsson, Roger
Format: Journal Article
Sprache:Englisch
Veröffentlicht: WASHINGTON Amer Chemical Soc 11.02.2016
Schlagworte:
Benzofurans - chemical synthesis
Benzofurans - chemistry
Benzofurans - pharmacology
Chemistry, Medicinal
Crystallography, X-Ray
Dose-Response Relationship, Drug
Humans
Life Sciences & Biomedicine
Models, Molecular
Molecular Structure
Nuclear Receptor Subfamily 4, Group A, Member 2 - agonists
Nuclear Receptor Subfamily 4, Group A, Member 2 - metabolism
Pharmacology & Pharmacy
Protein Multimerization - drug effects
Retinoid X Receptors - agonists
Retinoid X Receptors - metabolism
Science & Technology
Structure-Activity Relationship
TARGET
CELLS
ENANTIOSELECTIVE SYNTHESIS
MODELS
INCREASES
NURR1
DOPAMINERGIC-NEURONS
EXPRESSION
ALPHA-IODINATION
PARKINSONS-DISEASE
ISSN:0022-2623, 1520-4804, 1520-4804
Online-Zugang:Weitere Angaben
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Zusammenfassung: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 SAP, of sterically constricted benzofurans at RXR The established SAR, using whole cell functional assays, lead to the full agonist 9a at RXR. (pEC(50) of 8.2) and RXR-Nurr1. The X-ray structure shows enantiomeric discrimination where 9a optimally addresses the ligand binding pocket of RXR.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.5b01702