Development of a Brain-Penetrant Nurr1 Agonist Tool

Area of Science:

• Neuroscience
• Medicinal Chemistry
• Pharmacology

Background:

• Nuclear receptor-related 1 (Nurr1) is a ligand-sensing transcription factor involved in neuroprotection and implicated in neurodegenerative diseases.
• Existing Nurr1 ligands lack dedicated brain-targeting capabilities, limiting in vivo studies of Nurr1 activation in the central nervous system (CNS).

Purpose of the Study:

• To develop a potent, selective, and brain-penetrant Nurr1 agonist for investigating Nurr1's role in the CNS.
• To create a novel chemical entity based on the vidofludimus scaffold with improved brain-to-blood distribution.

Main Methods:

• Utilized scaffold-hopping from cyclopentene to thiophene.
• Incorporated enhanced fluorination and replaced a carboxylic acid with an amide group.
• Employed the dihydroorotate dehydrogenase (DHODH) inhibitor vidofludimus as a starting point.

Main Results:

• Successfully developed a novel Nurr1 agonist with a high brain-to-blood ratio.
• The resulting compound demonstrated high potency and selectivity for Nurr1.
• The new agonist exhibits excellent brain penetrance, suitable for CNS studies.

Conclusions:

• A highly potent, selective, and brain-penetrant Nurr1 agonist was synthesized.
• This novel compound is a valuable tool for studying Nurr1 activation in the CNS.
• The developed agonist overcomes limitations of previous Nurr1 ligands for brain-related research.