Development of a Potent Nurr1 Agonist Tool for In Vivo Applications

Nuclear receptor related 1 (Nurr1) is a neuroprotective
transcription
factor and an emerging target in neurodegenerative diseases. Despite
strong evidence for a role in Parkinson’s and Alzheimer’s
disease, pharmacological control and validation of Nurr1 are hindered
by a lack of suitable ligands. We have discovered considerable Nurr1
activation by the clinically studied dihydroorotate dehydrogenase
(DHODH) inhibitor vidofludimus calcium and systematically optimized
this scaffold to a Nurr1 agonist with nanomolar potency, strong activation
efficacy, and pronounced preference over the highly related receptors
Nur77 and NOR1. The optimized compound induced Nurr1-regulated gene
expression in astrocytes and exhibited favorable pharmacokinetics
in rats, thus emerging as a superior chemical tool to study Nurr1
activation in vitro and in vivo.