Identification of a series of highly potent activators of the Nurr1 signaling pathway.
The nuclear receptor Nurr1 (NR4A2) is critically involved in the development and maintenance of midbrain dopaminergic neurons and is believed to function independently of endogenous activation. The hit identification and SAR studies leading to isoxazolo-pyridinone 7e, a highly potent, brain penetrable activator of the Nurr1 signaling pathway, are described.
Hintermann
Samuel
S
Novartis Institutes for BioMedical Research, Neuroscience Research, CH-4002 Basel, Switzerland. samuel.hintermann@novartis.com
Chiesi
Michele
M
von Krosigk
Ulrike
U
Mathé
Danièle
D
Felber
Richard
R
Hengerer
Bastian
B
D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000819:agonists*; D007555:Isoxazoles / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011728:Pyridones / Q000737:chemistry* / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000819:agonists*
C519008:5-methyl-3-phenyl-6-(4-(2-methoxyethoxymethyl)phenyl)isoxazolo(5,4-c)pyridin-5H-4-one; D004268:DNA-Binding Proteins; D007555:Isoxazoles; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D011728:Pyridones; D014157:Transcription Factors